【エムガルティ皮下注 120mg オートインジェクター、皮下注
120mg シリンジ】に関する費用対効果評価 [第 1.0 版]【提出者名】日本イーライリリー株式会社【提出日】2022 年 1 月 14 日 (第 1.0 版の提出日【該当する場合のみ】)

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【 目次】

0. 要旨 ....................................................................................................................... 8
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 ...................................................................................................... 14
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..................................... 15
1.7 主な有害事象 ................................................................................................... 16
1.8 他国の医療技術評価機関における評価結果 ......................................................... 16
2. 費用効果分析における分析条件の設定 .................................................................... 23
2.1 分析対象とする集団 .......................................................................................... 23
2.2 比較対照.......................................................................................................... 23
2.3 分析の立場と費用の範囲 ................................................................................... 24
2.4 効果指標.......................................................................................................... 24
2.5 分析期間.......................................................................................................... 24
2.6 割引率 ............................................................................................................. 24
2.7 分析条件の設定の要約 ...................................................................................... 24
3. 追加的有用性 ........................................................................................................ 26
3.1 クリ ニカルクエスチョン ......................................................................................... 26
3.2 システマティックレビュー ...................................................................................... 27
3.2.1 臨床研究の組み入れ基準や除外基準 ............................................................ 27
3.2.2 使用したデータベース................................................................................... 36
3.2.3 使用した検索式............................................................................................ 36
3.2.4 システマティックレビューの実施 ...................................................................... 36
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].......... 54
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] ...... 54
3.5 既存データの再解析 .......................................................................................... 54
3.6 メタアナリシスの詳細[該当する場合のみ] .......................................................... 56

3.6.1 Meta-analyses methods.............................................................................. 56
3.6.2 Meta-analyses results ................................................................................ 56
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] ........................... 582

3.7.1 Indirect comparison methods ..................................................................... 58
3.7.2 Software .................................................................................................... 58
3.7.3 Indirect comparison results: base case........................................................ 58
3.8 追加的有用性の有無に関する評価 ...................................................................... 60
4. 分析方法の詳細 ..................................................................................................... 63
4.1 分析方法.......................................................................................................... 63
4.1.1 費用対効果の算出方法 ................................................................................ 63
4.1.2 モデルで使用した仮定.................................................................................. 68
4.2 分析で使用したパラメータ .................................................................................... 73
4.2.1 有効性･安全性等のパラメータの詳細 ............................................................. 76
4.2.1.1 Distribution parameters.......................................................................... 78
4.2.1.2 Mean change from baseline in monthly migraine headache days.............. 81
4.2.1.3 Response rates........................................................................................ 85
4.2.1.4 Persistency to oral preventive migraine treatment................................... 87
4.2.1.5 Discontinuation ...................................................................................... 91
4.2.1.6 Adverse events........................................................................................ 98
4.2.1.7 Mortality ................................................................................................ 98
4.2.2 QOL 値の詳細 ............................................................................................ 98
4.2.3 費用のパラメータの詳細 .............................................................................. 111
4.2.3.1 Cost and resource use ............................................................................ 111
4.2.3.2 Drug acquisition costs ............................................................................ 111
4.2.3.3 Resource use and unit costs.................................................................... 112
5. 分析結果.............................................................................................................. 116
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 ...... 116
5.1.1 基本分析の増分費用、増分効果、増分費用効果比.......................................... 116
5.1.2 感度分析................................................................................................... 118
5.1.2.1 専門組織の指示に基づく感度分析 ............................................................. 118
5.1.2.2 Deterministic sensitivity analyses (DSA) ................................................ 119
5.1.2.3 Probabilistic sensitivity analyses............................................................132
5.1.2.4 Scenario analysis ...................................................................................139
5.1.3 分析の妥当性の検討 ..................................................................................143
5.1.4 分析結果の解釈.........................................................................................143
5.1.5 価格調整率の重み [該当する場合のみ] ........................................................144
5.1.5.1 片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う患者と片頭痛予 防薬の 3
剤目の治療を中止した患者の割合 .........................................................................1443

5.1.5.2 EM と CM の患者割合 .............................................................................146
5.1.5.3 価格調整率の重み...................................................................................147
5.1.6 価格の引き上げ [該当する場合のみ] ............................................................147
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] ..............................147
5.3 その他の分析 [該当する場合のみ].....................................................................147
6. 再分析用のデータ ................................................................................................148
7. 実施体制..............................................................................................................149
8. 参考文献..............................................................................................................150

4

Abbreviation

Full description

AAN

American Academy of Neurology

ACE

Angiotensin-converting enzyme

ADA

Anti-drug antibodies

AE

Adverse event

AHS

American Headache Society

ARB

Angiotensin II receptor blocker

BSC

Best supportive care

C2H

Core2 Health

CADTH

Canadian Agency f or Drugs and Technologies in Health

CDSR

Cochrane Database of Systematic Reviews

CEAC

Cost ef f ectiveness acceptability threshold

CENTRAL

Cochrane Central Register of Controlled Trials

CFB

Change f rom baseline

CGRP

Calcitonin gene-related peptide

CI

Conf idence interval

CM

Chronic migraine

DSA

Deterministic sensitivity analysis

EANC

European Academy of Neurology Congress

EHF

European Headache FoundationEM

Episodic Migraine

EUCTR

EU Clinical trials register

GMB

Galcanezumab

HD

Headache days

HRQoL

Health-related quality of lif e

HTA

Health Technology Assessment

ICHD

International Classif ication of Headache Disorders

ICER

Incremental cost ef f ectiveness threshold

ICTRP

International Clinical Trials Registry Platf orm

IHSInternational Headache Society

ITC

Indirect Treatment Comparison

ITT

Intention to treat

5

JHS

Japanese Headache Society

JMACCT

Japanese Medical Association Center f or Clinical Trials

MFDS

Ministry of Food and Drug Saf ety

Mg

Milligram

MHD

Migraine headache days

MHLW

Ministry of Health, Labor and Welf are

MIBS

Migraine Interictal Burden Scale

MIDAS

Migraine Disability Assessment Scale

MSQ

Migraine-Specif ic Quality of Lif e

NDB

National Database of Health Insurance Claims andSpecif ic Health Checkups of Japan

NMA

Network meta-analysis

OnaA

OnabotulinumtoxinA

OUGL

Optimised used guidelines

PBAC

Pharmaceutical Benef its Advisory Committee

PHQ

Patient Depression Questionnaire

PICOS

Population, Intervention(s), Comparator(s), Outcome(s)and Study design

PMDA

Pharmaceutical and Medical Device Agency

PRISMA

Pref erred Reporting Items in Systematic Review andMeta-Analysis

PSA

Probabilistic sensitivity analysis

QALY

Quality adjusted lif e year

RCT

Randomized controlled trial

SAE

Serious adverse event(s)SDStandard deviation

SE

Standard error

SFHD

Symptom-f ree headache days

SLR

Systematic literature review

SoC

Standard of Care

WHO

World Health Organization

WPAI

Work Productivity and Activity Impairment

YLD

Years lost to disability

67

0. 要旨

分析対象技術名 [1.1 節]

エムガルティ皮下注 120mg オートインジェクター、皮下注
120mg シリンジ（ガルカネズマブ）
イギリス
NICE: Recommended with conditions
SMC: Recommended with conditions
フランス
HAS: SMR – important, ASMR – V

他国の医療技術評価機関にお ドイツ
ける評価結果 [1.8 節]

IQWiG: Hint of a considerable additional and No
additional benefit
カナダ
Recommended with conditions
オーストラリア
Recommended with conditions
対象疾患：片頭痛
以下の片頭痛患者をそれぞれ分析対象集団とする（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復対象とする疾患･集団 [2.1性片頭痛患者節]（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性
片頭痛患者（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者

比較対照技術名 [2.2 節]（ａ）（ｂ）:プロプラノロール（ｃ）（ｄ）: Best Supportive Care

分析の立場と費用の範囲

分析の立場は公的医療の立場、費用の範囲は公的医療費を用い[2.3 節]る

使用する効果指標 [2.4 節]質調整生存年(Quality-adjusted lif e year: QALY)を用いる

設定した分析期間 [2.5 節]

25 年

割引率 [2.6 節]

費用･効果ともに年率 2%を用いる

8

項目

内容
Adult (18+) patients (males and females) sufferingfrom migraine
All preventive pharmacological interventions for thetreatment of migraine relevant to JapanAll preventive pharmacological interventions for thetreatment of migraine relevant to Japan, compared toeach other or to placebo
Efficacy outcomes:• Monthly Migraine Headache Days
• Monthly Headache Days
• Monthly Migraine Headache Attacks• Monthly Headache Attacks• Monthly use of acute migraine treatment• 50% Reduction in Monthly Migraine Headachedays• 75% Reduction in Monthly Migraine Headachedays• 100% Reduction in Monthly Migraine Headachedays
HRQoL outcomes:• PGI-S score• MIDAS Total Score, Absenteeism Score,
Presenteeism Score, Days of lost productivity
Score• MSQoL Questionnaire (Total score, role functionpreventive, role function-restrictive, emotional
function domains)• EQ-5D Score

対象集団
介入
比較対照

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

アウトカム

節]

Safety and discontinuation outcomes:• AEs due to any cause• SAEs due to any cause• Discontinuation due to any cause• Discontinuation due to AEs• Discontinuation due to lack of efficacy
Phase II, III, IV randomised controlled trials(Crossover up to time of crossover)Conference abstracts from 2017-current
Language English and Japanese (other languages will
be excluded)
1946 年から 2021 年 10 月 29 日まで(Conference abstracts:2017-2021)

研究デザイン

文献検索期間同定された 195 件の結果より、ガルカネズマブのデータは７試験であった。このうち、日本人を対象とした試験と海外の第 3 相試験
システマティックレビュー結果（CGAG/CGAH/CGAI）のデータを含めてメタアナリシス及び間接の概要 [3.2/3.4 節]

比較に使用した。比較対照技術についてのデータはシステマティッ
クレビューから同定されず、別途定義された基準で採択し使用した。
（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛患者ガルカネズマブ 120mg はプロプラノロールに比較して統計的に間接比較の結果 [3.7 節]

有意な差を示した。 (mean dif ference:
) P=

(

)

（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性
片頭痛患者
ガルカネズマブ 120mg はプロプラノロールに比較して統計的に9

有意な差を示した。(mean difference:
P=

(

)

)

（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者
ガルカネズマブ 120mg は BSC に比較して統計的に有意な差を示した。(mean difference:
P

(

)

)

（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者
ガルカネズマブ 120mg は BSC に比較して統計的に有意な差を示した。(mean difference:
P

(

)

)

（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛患者■ 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）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性
片頭痛患者
追加的有用性の有無 [3.8

■ 追加的有用性あり □ 「追加的有用性なし」あるいは「あるとは節]判断できない」（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者■ 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」（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者■ 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」本分析はガルカネズマブとプロプラノロールまたは Bestsupportive care の治療の費用対効果を評価するためセミマル
コフモデルにより費用対効果分析を実施した。マルコフモデルの健康状態は、①3 ヵ月目の反応評価前の治療中、②反応評価後の費用対効果の分析方法の概治療中（4 ヵ月目以降）、③治療中止、④死亡の 4 つからなり、そ要 [4.1.1 項、4.2 節等]

れぞれの健康状態は、月あたりの片頭痛日数と関連して設定されている。それぞれガルカネズマブ、プロプラノロール、best
supportive care の治療開始時に「①3 ヵ月目の反応評価前の治療中」となり、その 3 か月間後に、治療への反応性をもとに
responder または non-responder に分類し（response

10assessment）、responder はその後それぞれの治療を継続するが(「②反応評価後の治療中（4 ヵ月目以降）」への移行)、nonresponder は「③治療中止」に移行する(図 4-1 参照)。その後
は 1 ヵ月サイクルで健康状態が移行する。Response
assessment 前後いずれにおいても、有害事象等を想定した所定の割合に応じ「③治療中止」に移行する。いずれの状態からも、国民の標準死亡率に従い死亡する。また、Distribution
approach を用い、費用と QALY それぞれが持つ非線形な関係性をモデル化した。
（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛患者
ベースケースにおける ICER が¥6,077,875 であり、500 万円
以上 750 万円以下の区間にあると判断された。
（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性
片頭痛患者
結果の概要 [5.1 節]

ベースケースにおける ICER が¥2,691,706 であり、500 万円/QALY 以下の区間にあると判断された。
（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者
ベースケースにおける ICER が¥2,850,240 であり、500 万円/QALY 以下の区間にあると判断された。
（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者
ベースケースにおける ICER が¥1,441,739 であり、500 万円/QALY 以下の区間にあると判断された。
（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛患者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（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性11

片頭痛患者


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（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者


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（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者


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

12

1. 対象となる医薬品･医療機器の性質
1.1 名称･ 販売名：エムガルティ皮下注 120mg オートインジェクター、皮下注 120mg シリンジ
･ 一般名：ガルカネズマブ（遺伝子組換え）
1.2 保険償還価格
本剤は 2021 年 4 月 21 日に薬価収載された。詳細は以下のとおりである。
表 1-1 薬価の算定方式
算定方式
原
価
計
算

製品総原価
営業利益
流通経費
消費税
補正加算
外国平均価格調整
算定薬価

原価計算方式オ ー ト イ ン ジ ェ ク タ ー シリンジ（120mg1mL1 筒）（120mg1mL1 キット）
31,530 円
32,197 円
5,477 円
5,593 円
3,001 円
3,064 円
4,001 円
4,085 円なし
（調整前）44,008 円 →なし（調整後）45,165 円
エムガルティ皮下注 120mg オ エムガルティ皮下注 120mg シートインジェクター
リンジ（120mg1mL1 キット）
（120mg1mL1 筒）45,165 円
44,940 円

1.3 治療効果のメカニズム
本薬は、カルシトニン遺伝子関連ペプチド（Calcitonin-gene related peptide：CGRP）に結合する遺伝子組換えヒト化 IgG4 モ ノ クロ ーナル抗 体である。 本 薬は CGRP に 高 い 親 和 性（KD=31pM）と選択性を有し、CGRP 受容体や CGRP 関連ペプチド（アドレノメデュリン、アミ リ ン、
カルシトニン及びインテルメジ ン）には明らかな結合性を示さない（CGRP に対する親和 性はこれ
らペプチドに対する親和性の 10000 倍より大きい）。CGRP は主に三叉神経節で発現 する神経ペプチドで、血管拡張、炎症促進、侵害受容における役割がある。片頭痛患者では血中 CGRP 濃度が上昇しており、片頭痛患者に CGRP を投与すると片頭痛発作が誘導される。したがって、 本品の CGRP 活性の阻害作用により、片頭痛発作の発症を抑制することが期待される。
1.4 対象疾患
本品の効能または効果は、以下のとおりである（添付文書より抜粋 1）
片頭痛発作の発症抑制、ただし、以下の場合に限る。
(a) 前兆のある又は前兆のない片頭痛の発作が月に複数回以上発現している、又は 慢性
片頭痛である(b) 非薬物療法、片頭痛発作の急性期治療等を適切に行っても日常生活に支障をきたしている患者･ 分析対象とする疾患の疫学的性質(有病率、新規発症者数、好発年齢等)
1 国際頭痛分類 (ICHD) を用いた日本での疫学研究では、 日本人の片頭痛 有 病 率 は8.4%で、男女比（女/男）が約 3.6 と推定され 2、 30 歳代及び 40 歳代の女性における片頭痛の有病率は男性の有病率に比べて高いことが知られている 3。また、反復性片頭痛と慢性片頭痛は発作の頻度で区別されるが、片頭痛としての病態に差異はないと考え ら れ、
13

2

実際、疫学調査の結果では 1 年あたり 2.5%の反復性片頭痛患者が慢性片頭痛 に移行したという報告 4がある一方で、2 年間の観察で慢性片頭痛患者の 26%が反復性片頭痛等へ寛解したという報告 5もある。これらの報告は反復性片頭痛と慢性片頭痛が互いに 行き
来する 2 つの状態であることを示している。
片頭痛は男女とも 20～50 歳代の勤労世代に多く見られる疾患であること 2 から生産性の低下による経済的損失による医療経済への影響が無視できない。その中でも、片頭痛は30 歳代から 40 歳代の女性を中心とする若年者に有病率が高く、これらの年齢 層に おいてとくに日常生活及び社会生活に支障をきたす疾患である。頭痛による生産性の低下により 、
毎年 2880 億円の経済的損失が日本経済にもたらされていると推定されている 6。

･ 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 4.8 万人である。
･ 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
株式会社 MDV の医療機関ベースのレセプトデータから、上市以降、本剤が使用された患者数 を
年齢・性別に分けて下記に示す（表 1-2）。40 歳代の女性に最も多く使用されているが、 片頭痛の有病率と同じく 30-50 歳代の女性に広く使用されている。
表 1-2 2021 年 4 月から 2021 年 9 月までに本剤が使用された患者数
年齢

男性

女性

総計

年齢割合

18-29 歳

22

69

91

11%

30-39 歳

31

131

162

19%

40-49 歳

51

218

269

32%

50-59 歳

29

162

191

23%

60-69 歳

14

77

91

11%

70-79 歳

2

30

32

4%

80-89 歳

3

2

5

1%

90 歳以上

0

0

0

0%

総計

152

689

841

100%

男女割合

18%

82%

100%

NA

出典： MDV Analyzer
1.5 使用方法等【医薬品】
本品の用法及び用量は、通常、成人にはガルカネズマブ（遺伝子組換え）として初回に 24 0m g
を皮下投与し、以降は１ヵ月間隔で 120mg を皮下投与する。本品使用時の概要は下記のと おりである。
表 1-3 使用方法
投与経路
投与方法
投与量
投与頻度

皮下投与
単独で使用する
初回 240mg、以降 120mg
1 か月間隔14

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
1.6.1 片頭痛の分類
片頭痛は一次性頭痛のなかで最も臨床的に重要な疾患である。典型的には、片側性で拍動性の中等度から重度の頭痛発作が繰り返し生じ、発作は 4～72 時間持続する。頭痛に加えて、 悪心、嘔吐、光過敏、音過敏などを伴うことも多く、日常動作で頭痛が増悪するため生活に大きな支障 をきたす。国際頭痛分類ではこれらの臨床的特徴をもって片頭痛の診断基準としている。 片頭痛患者では片頭痛発作に先立って前兆と呼ばれる特徴的な症状が自覚されることがあり、 片頭痛は前兆の種類や有無によって更に分類される。また、片頭痛はその頭痛発作の頻度によっても分類され、3 ヵ月にわたり月に 4 日から 14 日以内の頻度で片頭痛がみられた場合には反復性片頭痛と分類される。また、片頭痛のうち、3 ヵ月にわたり月に 15 日以上の頻度で頭痛がみられ、 少なくとも月に 8 日の頭痛が片頭痛の特徴を持つ場合には慢性片頭痛と分類され、反復性片頭痛と区別される。
国際頭痛分類（ICHD 第 3 版）は、日本頭痛学会により日本語訳がなされ臨床現場に広く使用されている 7。
1.6.2 片頭痛治療における本剤の位置づけ
片頭痛治療には、頭痛発作の痛みを軽減するための急性期治療と頭痛発作の回数自 体 を軽減する予防療法の２つに大別される。2021 年 10 月に刊行された頭痛の診療ガイドライン 2021 8において予防療法は片頭痛発作が月に２回以上、 あるいは生活に支障をきたす頭痛が 月に３日以上ある患者、および急性期治療のみでは片頭痛発作による日常生活の支障がある 患者では予防療法の実施の検討が推奨されている。また，急性期治療のみでは片頭痛発作によ る日常生
活の支障がある場合、急性期治療薬が使用できない場合、永続的な神経障害をきたす おそれのある特殊な片頭痛に対しても予防療法が推奨されている。
本剤は大規模臨床試験でプラセボに対して有意な片頭痛予防効果が示されていることから、 既に
上述の診療ガイドラインにおいて片頭痛の新規予防療法として推奨の強さは強い/弱い の 2 段階
で「強い」、エビデンスの確実性は A-C の 3 段階で「A」、 薬効の group は 1（有効）から 5（無効）の 5 段階で「1（有効）」に位置づけられている。
1.6.3 最適使用推進ガイドラインにおける本剤の使用基準＜施設について＞
本品が適応となる患者の選択及び投与継続の判断は、適切に行われることが求められ、 本剤の投与に際しては適切な片頭痛とそれ以外の頭痛疾患を鑑別することが必要である。 また、本剤の投与により重篤な副作用が発現した際にも適切な対応をすることが必要なため、① ～③ の全てを満たすことが最適使用推進ガイドラインにおいて記載されている。以下に一部抜粋して示す。
• 片頭痛の病態、経過と予後、診断、治療（参考：慢性頭痛の診療ガイドライン 2013 9）を熟知し、本剤についての十分な知識を有している医師（医師要件あり ※）が本剤 に関 する治療責任者として配置されていること、また、二次性頭痛との鑑別のために MRI 等による検査が必要と判断した場合、専門医との連携体制が整っている施設であること。
• 院内の医薬品情報管理体制が整っている。
• 当該施設又は近隣医療機関の専門性を有する医師と連携し、副作用の診断や対応に関して指導及び支援を受け、副作用の診断対応に関して直ちに適切な処置ができる等の体制が整っている。
※＜医師要件＞ 以下の基準を満たすこと。
1. 医師免許取得後 2 年の初期研修を修了した後に、頭痛を呈する疾患の診療に 5 年以上の臨床経験を有していること。
2. 本剤の効果判定を定期的に行った上で、投与継続の是非についての判断を適 切に行うことができること。
15

3. 頭痛を呈する疾患の診療に関連する以下の学会の専門医の認定を有していること。
・日本神経学会 ・日本頭痛学会 ・日本内科学会（総合内科専門医） ・日本脳神経外科学
会＜投与対象となる患者＞
最適使用推進ガイドライン 10では、投与対象となる患者を以下のように記載している。
【患者選択について】投与の要否の判断にあたっては、以下の 1.～4.のすべてを満たす患者としている。
・ 国際頭痛分類（ICHD 第 3 版）を参考に十分な診療を実施し、前兆のある又は前兆のな い片頭痛の発作が月に複数回以上発現している、又は慢性片頭痛であることが確認されてい る。
・ 本剤の投与開始前 3 カ月以上において、1 カ月あたり の Migraine headache days
(MHD)が平均 4 日以上である。
・ 睡眠、食生活の指導、適正体重の維持、ストレスマネジメント等の非薬物療法及び片 頭痛発
作の急性期治療等を既に実施している患者であり、それらの治療を適切に行っても日 常生
活に支障をきたしている。
・ 本邦で既承認の片頭痛発作の発症抑制薬（プロプラノロール塩酸塩、バルプロ酸ナトリ ウム、
ロメリジン塩酸塩等）のいずれかが、下記①～③のうちの 1 つ以上の理由によって 使用又は継続できない。
①効果が十分に得られない②忍容性が低い③禁忌、又は副作用等の観点から安全性への強い懸念がある【投与の継続・中止について】
本剤投与中は症状の経過を十分に観察し、 本剤投与開始後 3 カ月（3 回投与後）を目安に治療上の有益性を評価して症状の改善が認められない場合には、本剤の投与中止を考慮す ること。
またその後も定期的に投与継続の要否について検討し、頭痛発作発現の消失・軽減等 により 日
常生活に支障をきたさなくなった場合には、本剤の投与中止を考慮すること。
なお、日本人を対象とした臨床試験において、本剤の 18 カ月を超える使用経験はない。

1.7 主な有害事象
本剤の主な有害事象として、リスク管理計画書に示された重篤な有害事象（重要な特定され たリスク）は重篤な過敏症である。
モノクローナル抗体の投与は過敏症反応を引き起こす可能性があり、実臨床下において、 ア ナフィラキシー反応を含む重篤な過敏症は、迅速かつ適切な処置を施さないと生命に危険 が及ぶ可能性があることから、本品のベネフィット・リスクプロファイルに重大な影響を及ぼし得ると考えられる。これまでに実施した本剤の国内臨床試験で認められた主な過敏症は、 蕁麻疹、発疹、 そう痒症であり、重症度はその多くが軽度から中等度で、ア ナフィラキシ ー反応を含む重篤な 過敏症は認められなかった。一方、海外の製造販売後の自発報告においては本薬との因果関係が否 定できない過敏症として、アナフィラキシ ー、血管性浮腫、発疹等の発現が報告されているが、 重 篤な過敏症の発現割合は低く、死亡例は報告されていない。
1.8 他国の医療技術評価機関における評価結果
表 1-4 主要国における評価の一覧表
機関名
国名評価結果 (記載例)

リスト価格
(現地通貨
建)
16

イギリス

NICE

SMC

フランス

HAS

ドイツ

IQWi
G

カナダ

CADT
H

オーストラリア

PBAC･Recommended with conditions(specifically: Galcanezumab isrecommended as an option for preventing
migraine in adults, only if:
1. they have 4 or more migrainedays a month
2. at least 3 preventive drug
treatments have failed and3. the company provides it
according to the commercial
arrangement･ Evaluation status: final guidance (18November 2020)･ Recommended with conditions(specifically: for the treatment of patientswith chronic and episodic migraine whohave had prior failure on three or moremigraine preventive treatments. This
advice applies only in the context of an
approved NHS Scotland Patient Access
Scheme･ Evaluation status: final guidance (12April 2021)･ SMR: important･ ASMR: V･ efficiency evaluation: not performed£450.00(without
VAT)･ Hint of a considerable additional and No
additional benefit• Subpopulation A: For naive patientsand patients that have failed/not
tolerated at least 1 prophylactic
treatment→ No added benefit• Subpopulation B: Patients thathave failed the following substanceclasses: Metoprolol/propranolol,
topiramate, amitriptylin, flunarizine→ No added benefit• Subpopulation C: Patients thatfailed all other treatments(substance classes)→ Hint of a considerable
additional benefit･ Recommended with conditions€ 490.21･ Recommended with conditions

Not
availableNotavailable
yet$AUD
559.02【各国における費用対効果評価の詳細】
17

1. 評価の有無の一覧
表 1-5 評価の有無の一覧
機関名
国名
イギリス
NICE
SMC
フランス
HAS
ドイツ
IQWiG
カナダ
CADTH
オーストラリア
PBAC

評価結果の有無
あり
あり
あり
あり
あり
あり

2. 評価結果の詳細
表 1-6 評価結果の詳細
国名
機関名
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、その条件の詳細イギリス（イングランド/ウェールズ）NICE
https://www.nice.org.uk/guidance/ta659/chapter/1Recommendations
ガルカネズマブ
Recommended with conditions
Galcanezumab is recommended as an option forpreventing migraine in adults, only if:
1. they have 4 or more migraine days a month
2. at least 3 preventive drug treatments havefailed and3. the company provides it according to thecommercial arrangement.
•

Stop galcanezumab after 12 weeks oftreatment if:

in episodic migraine (less than 15
headache days a month) the frequency
does not reduce by at least 50%
in chronic migraine (15 headache days a month ormore with at least 8 of those having features of
migraine) the frequency does not reduce by at least30%.
Episodic and chronic migraine in patients who havea history of at least 3 prior preventive treatment
failures
The recommended dose is 120 mg galcanezumab
injected subcutaneously once monthly, with a 240
mg loading dose as the initial dose.
Best supportive care for episodic migraine, andbotulinum toxin type A and best supportive care forchronic migraine
Episodic migraine compared to BSC: £22,633
Chronic migraine compared to BSC: £8,796
Chronic migraine compared to Botox: £15,636•

評価対象疾患使用方法 (※)

比較対照

主要な増分費用効果比の値

18

国名
機関名
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、その条件の詳細評価対象疾患使用方法 (※)

比較対照
主要な増分費用効果比の値
国名
機関名
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、その条件の詳細評価対象疾患使用方法 (※)

比較対照

イギリス（スコットランド）
SMC
https://www.scottishmedicines.org.uk/medicinesadvice/galcanezumab-emgality-full-smc2313/
ガルカネズマブ
Recommended with conditions
For the treatment of patients with chronic andepisodic migraine who have had prior failure on
three or more migraine preventive treatments. The
treatment benefit should be assessed within 3months after initiation of treatment. Any further
decision to continue treatment should be taken on
an individual patient basis. Evaluation of the needto continue treatment is recommended regularly
thereafter. Treatment should be initiated byphysicians experienced in the diagnosis andtreatment of migraine.
Episodic and chronic migraine in patients who havea history of at least 3 prior preventive treatment
failures
The recommended dose is 120 mg galcanezumab
injected subcutaneously once monthly, with a 240
mg loading dose as the initial dose.
Erenumab, fremanezumab
N/A (費用効果分析は行われなかった)
フランス
HAS
Haute Autorité de Santé - EMGALITY (has-sante.fr)
ガルカネズマブ
Recommended with conditions
Favourable opinion for reimbursement in patientswith severe migraine who have at least 8 migrainedays per month, with previous failure to at least
two prophylactic treatments and without
cardiovascular disease (patients having had amyocardial infarction, unstable angina, coronary
artery bypass graft (CABG), percutaneous coronary
intervention (PCI), stroke, deep-vein thrombosis(DVT) or other serious cardiovascular risk).
High-Frequency Episodic and chronic migraine
patients with a treatment history of at least 2 prior
failures
The recommended dose is 120 mg galcanezumab
injected subcutaneously once monthly, with a 240
mg loading dose as the initial dose.
Best supportive care (trial) in the clinical19

主要な増分費用効果比の値
国名

ドイツ

機関名
評価結果の
URL などIQWiG

assessment
N/A

https://www.gba.de/bewertungsverfahren/nutzenbewertung/450/#english

評価対象技術評価結果

ガルカネズマブ
Population A: Additional benefit not proven.
Population B: Additional benefit not proven.
Population C: Hint for a considerable additional benefit
条件付き推奨の Generally, the entire label population is reimbursed in
場合は、その条 Germany, ie. EM and CM patients with 4+ MHDs. However, wedidn’t show an additional benefit in the naïve patients or
件の詳細
those who failed only 1 or 2 treatments, hence the German
authorities provided a guidance (treatment advice)highlighting that Galca has only shown a benefit in the more
severe patient population as highlighted by Julie below.
Physicians can prescribe outside of this treatment advice but
may be penalised if they are audited, especially if they cannot
provide/ a rationale on why they prescribed outside of thetreatment advice. However, this budget audit is done on a
subnational level and more a control mechanism for budget
purposes. Since the audit can lead to financial payback
requirements of the physician to the statutory healthinsurance and it is very administrative heavy, you will findthat a lot of the physician follow the treatment advice to
avoid a potential audit. However, despite this advice theentire label is reimbursed.
評価対象疾患• Subpopulation A: Naive patients and patients that havefailed/not tolerated at least 1 prophylactic treatment• Subpopulation B: Patients that have failed the following
substance classes: Metoprolol/propranolol, topiramate,amitriptylin, flunarizine
Subpopulation C: Patients that failed all other treatments(substance classes)
The recommended dose is 120 mg galcanezumab injected
使用方法 (※)
subcutaneously once monthly, with a 240 mg loading dose as
the initial dose.
比較対照 Subpopulation A: Metoprolol or propranolol or flunarizineor topiramate or amitriptyline, taking into accountmarketing authorization and the previous therapy
 Subpopulation B: Valproic acid1 or Clostridium botulinum
toxin type A2
 Subpopulation C: Best supportive care
1 . According to Annex VI to Section K of the Pharmaceuticals

Directive: if treatment with any other authorised medicinal

20

product has not been successful or is contraindicated.
2 . According to the marketing authorisation for chronic
migraines.
主要な増分費用効果比の値
国名機関名
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、その条
件の詳細評価対象疾患使用方法 (※)

N/A(費用効果分析は行われていない)
カナダ
CADTH
https://www.cadth.ca/sites/default/files/DRR/2021/SR0693%
20Emgality%20-%20CADTH%20Final%20Rec.pdf
ガルカネズマブ
Recommended with conditions
1. The patient has a confirmed diagnosis of episodic or
chronic migraine according to the International Headache
Society criteria, defined as either of the following:
1.1. Episodic migraine: migraine headaches on at least 4 days
per month and less than 15 headache days per month formore than 3 months.
1.2. Chronic migraine: headaches for at least 15 days permonth for more than 3 months of which at least eight days
per month are with migraine
2. The patient has experienced an inadequate response,
intolerance, or contraindication to at least two oral
prophylactic migraine medications of different drug classes.
3. The physician must provide the number of headache andmigraine days per month at the time of initial request for
reimbursement.
4. The maximum duration of initial authorization is six
months.
5. The physician must provide proof of beneficial clinicaleffect when requesting continuation of reimbursement,
defined as a reduction of at least 50% in the average numberof migraine days per month at the time of first renewal
compared with baseline. At subsequent renewals thephysician must provide proof that the initial 50% reduction in
the average number of migraine days per month has been
maintained.
6. The maximum duration of subsequent authorizations
following the initial authorization is six months
7. The patient should be under the care of a physician who
has appropriate experience in the management of patientswith migraine headaches.
8. Galcanezumab should not exceed the drug program cost oftreatment with the least expensive CGRP inhibitor for thetreatment of migraine.
Episodic and chronic migraine at least 2 prior preventive
treatment.
Approved dose is a loading dose of 240 mg (administered as
2 consecutive injections) followed by once monthly doses of
120 mg (1 injection).
21

比較対照
主要な増分費用
効果比の値

国名
機関名
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、その条
件の詳細評価対象疾患使用方法 (※)

比較対照

主要な増分費用
効果比の値

Best supportive care
CADTH re-analysis:
Episodic migraine, ≥2 prior preventative therapies: ICER =$273,560 per QALY
Chronic migraine, ≥ 2 prior preventative therapies: ICER =$109,325 per QALY
オーストラリア
PBAC
Pharmaceutical Benefits Scheme (PBS) | Galcanezumab(chronic migraine): Injection 120 mg in 1 mL pre-filled pen;
Emgality®
ガルカネズマブ
Recommended with conditions
Treatment criteria:Must be treated by a neurologist
Clinical criteria:
Patient must have experienced an average of 15 or moreheadache days per month, with at least 8 days of migraine,over a period of at least 6 months, prior to commencement oftreatment with this drug for this condition
AND
Patient must have experienced an inadequate response,
intolerance or a contraindication to at least three prophylactic
migraine medications prior to commencement of treatment
with this drug for this conditionAND
The treatment must not be in combination with botulinum
toxin
AND
Patient must be appropriately managed by his or herpractitioner for medication overuse headache, prior toinitiation of treatment with this drug
Chronic migraine in patients who have a treatment history ofat least 3 prior preventive treatments
The recommended dose is 120 mg galcanezumab injectedsubcutaneously once monthly, with a 240 mg loading dose as
the initial dose.
Chronic migraine: Botulinum toxin type A and best supportive
care
N/A

22

2. 費用効果分析における分析条件の設定

2021 年 8 月 27 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枠 組みについて以下に示す。
2.1 分析対象とする集団
2021 年 8 月 27 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とする集団について以下に示す。
以下の片頭痛患者をそれぞれ分析対象集団とする。
（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛患者（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性片頭痛患者（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者
2.2 比較対照
2021 年 8 月 27 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と選定理由（追加提供のナショナルデータベース （NDB）の共同解析の結果を含む）について以下に示す。
分析対象とする集団

比較対照技術名（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛患者（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性片頭痛患者

主に 2 剤目・3 剤
目に用いられる既存の片頭痛予防薬（プロプラノロー
ル、バルプロ酸）のうち、最も安価
なもの（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭
痛患者

Best
Supportive
Care

比較対照技術を選定した理由「 慢性頭痛の診療ガイドライン 20139 」によると、片頭痛予防薬で十分な効果が得られなかった場合、有効性の観点 から
他の予防薬に切り替えて治療を 行う ことが推奨される一方で、 予防薬の有効性の優劣や使用順序は明確に示されていない。このことは臨床専門家への 聴取結果によっても支持された。1 剤目にロメリ
ジ ンが多く 使用されていること等を踏まえ、当該分析対象集団の比較 対 照技術
は既存の片頭痛予防薬（プロプラノロー
ル、バルプロ酸）のうち最も安価な ものとすることが適当であると考えられる。
当該患者集団では保険適用のある片頭痛予防薬の選択肢が限られるため、Best Supportive Care を比較対照技
術とすることが適当であると考えられる。

また、本剤の費用対効果評価にかかる分析枠組みの中で、感度分析として以下のシ ナリ オ分析を行うことが指示された。
1. 片頭痛予防薬の２剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のた め使用できない反復性片頭痛患者
2. 片頭痛予防薬の２剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のた め使用
できない慢性片頭痛患者
3. 片頭痛予防薬の３剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のた め使用
23

できない反復性片頭痛患者
4. 片頭痛予防薬の３剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のた め使用
できない慢性片頭痛患者
それぞれの分析対象集団に対して、以下の比較対照技術とする。
・分析対象集団1および2:既存の片頭痛予防薬（ プロプラノロール、バルプロ酸）のうち、 当該集団に対して禁忌ではないもの
・分析対象集団 3 および 4: Best Supportive Care
従って、比較対照技術を選定する目的で、片頭痛予防薬の 1 人 1 日あたりの使用量に関 する
NDB の共同解析を実施した。NDB の 2021 年 3 月の 1 か月分のレセプトデータを使用し、 他の疾患の傷病名がないが片頭痛の傷病名（ ICD10: G43）のある症例を対象とし、 片頭痛 に適用のある予防薬それぞれの 1 人 1 日あたりの使用量を集計した。その際、添付文書上の最大使用量の 2 倍を超えている症例を解析対象から除外した。その結果、1 日あたりの薬価の平均値はそ
れぞれ、バルプロ酸が 36.3 円、プロプラノロールが 29.5 円、中央値はバルプロ酸が 36.4 円、プロプラノロールが 23.2 円となったため、上記表の「最も安価なもの」はプロプラノロールであると科学院と合意した。比較対照技術（プロプラノロール）の使用方法は下記の通りである。
比較対照技術（プロプラノロール）の使用方法
項目
投与経路
投与方法

投与頻度
平均処方量
*NDB のレセプトデータによる平均処方量

内容経口
1 日 20～30mg より投与をはじめ、効果が不十分な場合は 60mg まで漸増し、1 日 2 回あるいは 3 回に分割経口投与する （成人）毎日
*25.4 mg/日

従って、対象集団（ａ）（ｂ）の比較対照技術はプロプラノロール、感度分析 1 および 2 の比較対照
技術はバルプロ酸で合意した。
2.3 分析の立場と費用の範囲
HTA ガイドラインに基づき、分析の立場は公的医療の立場、費用の範囲は公的医療費とした。
2.4 効果指標
HTA ガイドラインに基づき、効果指標は QALY とした。
2.5 分析期間HTA ガイドラインに基づき、分析期間は 25 年に設定した。
2.6 割引率
HTA ガイドラインに基づき、割引率は費用･効果ともに年率 2%とした。
2.7 分析条件の設定の要約･ 下表にしたがい、分析を実施する集団ごとに 2.1 節から 2.6 節までの内容をまとめる。
分析対象とする集団（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反
復性片頭痛患者

24

比較対照
比較対照を選定した理由

分析の立場と費用の範囲
効果指標
分析期間
割引率

（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性片頭痛患者（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者（ａ）（ｂ）:プロプラノロール（ｃ）（ｄ）: Best Supportive Care（ａ）（ｂ）: 「慢性頭痛の診療ガイドライン 2013」によると、片頭痛予防薬で十分な効果が得られなかった場合、有効性の観点か
ら他の予防薬に切り替えて治療を行うことが推奨される一方で、予防薬の有効性の優劣や使用順序は明確に示されていない。このことは臨床専門家への聴取結果によっても支持された。1 剤目にロメリジンが多く使用されていること等を踏まえ、当該分析対象集団の比較対照技術は既存の片頭痛予防薬（プロプラノロール、
バルプロ酸）のうち最も安価なものとすることが適当であると考えられる。従って、片頭痛予防薬の使用量に関する NDB 共同解析を行い、プロプラノロールが比較対象技術として選定された。
（ｃ）（ｄ）: 当該患者集団では保険適用のある片頭痛予防薬の選択肢が限られるため、Best Supportive Care を比較対照技術とすることが適当であると考えられる。
分析の立場は公的医療の立場、費用の範囲は公的医療費
質調整生存年（Quality-adjusted lif e year: QALY）
25 年
費用･効果ともに年率 2%25

3. 追加的有用性
片頭痛に対して診療ガイドラインで推奨されている薬剤に対して広く国内外のエ ビデンス を網羅するべく、英語及び日本語によるシスマテ 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」と規定されているが、分析提出までの期間が非常に限られていることから、20 20 年
2 月 21 日に 3.2.2 に記載の海外の文献データベース（MEDLINE, EMBASE など）で、2020
年 3 月 12 日に 3.2.2 に記載の国内の文献データベース（医中誌など）においてシステマテ ィッ ク
レビューを実施し、分析枠組みの合意後の 2021 年 10 月 29 日に前回実施以降に更新された
国内と海外の文献に基づきシステマティックレビューを実施、更新した。なお、2020 年に実施したシステマティックレビューでは該当する対象集団を含む臨床試験の数が限定的であったため、 クリ
ニカルクエスチョンの「研究デザイン」 を観察研究としたシステマティックレビューも別途 2020 年 5
月 7 日に実施し、分析枠組みの決定後の 2021 年 10 月 29 日にシステマティックレビュ ー を実施、更新した。ガルカネズマブに関しては、システマティックレビューの結果から同定された試験のうち、対象集団が含まれている試験および日本人を対象とした試験の社内データを追加的有用性の評価に用いた。プロプラノロールに関しては、システマティックレビュ ーで同定された試験にガル
カネズ マブとの直接比較がなかったことと有効性のア ウトカムが異なっていたため、 PIC OS（ (PICOS):Population, Intervention(s), Comparator(s), Outcome(s) and Study
design）の対象集団の条件を変更して abstract screening から再度実施した。なお、観察研究についてはシステマティックレビューの結果、今回の対象となる試験が同定されなかったた め組み
込まれていない（同定された 1 文献は Botulinum toxin を対象としていた）。
以下に詳細を述べる。
3.1 クリ ニカルクエスチョン
RCT を対象としたシステマティックレビューのクリニカルクエスチョンは表 3-1 の通り設定した。
表 3-1 クリニカルクエスション
項目
対象集団
介入
比較対照

アウトカム

内容
Adult (18+) patients (males and f emales) suffering
f rom migraine
All preventive pharmacological interventions f or thetreatment of migraine relevant to JapanAll preventive pharmacological interventions f or thetreatment of migraine relevant to Japan, compared toeach other or to placebo
Ef f icacy outcomes:• Monthly Migraine Headache Days
• Monthly Headache Days
• Monthly Migraine Headache Attacks• Monthly Headache Attacks• Monthly use of acute migraine treatment• 50% Reduction in Monthly Migraine Headachedays• 75% Reduction in Monthly Migraine Headachedays• 100% Reduction in Monthly Migraine Headachedays
HRQoL outcomes:• PGI-S score

26

•
•
•

研究デザイン

文献検索期間MIDAS Total Score, Absenteeism Score,
Presenteeism Score, Days of lost productivity
Score
MSQoL Questionnaire (Total score, role f unctionpreventive, role f unction-restrictive, emotional
f unction domains)
EQ-5D Score

Saf ety and discontinuation outcomes:• AEs due to any cause• SAEs due to any cause• Discontinuation due to any cause• Discontinuation due to AEs• Discontinuation due to lack of ef ficacy
Phase II, III, IV randomised controlled trials(Crossover up to time of crossover)Conf erence abstracts from 2017-current
Language English and Japanese (other languages will
be excluded)
1946 年から 2021 年 10 月 29 日まで(Conf erence abstracts:2017-2021)

3.2 シ ステ マティックレビュー
3.2.1 臨床研究の組み入れ基準や除外基準
システマティックレビューの主な組み入れ基準と除外基準を以下に示す。なお、 今回は 臨床試験を対象とした 2020 年 2 月 21 日の海外文献データベース、2020 年 3 月 12 日の国内文献データベース、2021 年 10 月 29 日に実施した双方のアップデートおよび観察研究を対象とした2020 年 5 月 7 日、2021 年 10 月 29 日に実施したアップデートでの検索に対して、同じ基準 を
用いた。

27

表 3-2 Study selection criteria f or randomised controlled trials

TREATMENT/INTERVENTIONPOPULATION

Criteria
Inclusion
Exclusion
Abstract selection •Adult (18+) patients (males and females) suffering from•
Pediatric populations will be excluded
migraine.
•
Patients may suffer from either episodic or chronic forms of
migraine with or without other additional headache conditions,such as cluster headache
Full-text selection •Adult (18+) patients (males and females) suffering from
migraine.
•
Patients may suffer from either episodic or chronic forms of
migraine; or from other additional headache conditions, such as
cluster headache.
Abstract & full•
All preventive pharmacological interventions for the treatment of •Acute therapies not concomitant to any
text selection
migraine relevant to Japan, including:preventive therapies•
Antiepileptic drugs (Valproic acid, topiramate, gabapentin,•
Non-invasive therapies (e.g. physicallevetiracetam)
therapy)•
Beta-blockers (Atenolol, metoprolol, nadolol, propranolol)•
Alternative therapies (e.g. Chinese herbs)•
Antidepressants (Amitriptyline)•
Devices•
Calcium channel blockers (Verapamil, lomerizine)•
ARB/ACE inhibitors (Lisinopril, candesartan)•
CGRP receptor antagonists (Erenumab, galcanezumab,
fremanezumab)•
Others (Botulinum toxin type A, magnesium preparation,
tizanidine)Inclusion•
Interventions above compared to each other, or to placebo

OUTCOM
ES

COMPARATOR

Criteria
Abstract & fulltext selection

Abstract selection•

No selection on outcomesExclusion•
If multiple arms in RCT, at least twoarms need to be of interest (forexample, a 3-arm RCT comparing acutevs. preventive vs. placebo will be
included whilst only data from thepreventive and placebo arm are ofinterest.)•

No selection on outcomes29

Criteria
Inclusion
Full-text selection•
Efficacy outcomes:•
Monthly Migraine Headache Days*•
Monthly Headache Days*•
Monthly Migraine Headache Attacks*•Monthly Headache Attacks*•Monthly use of acute migraine treatment*•
50% Reduction in Monthly Migraine Headache days•
75% Reduction in Monthly Migraine Headache days•
100% Reduction in Monthly Migraine Headache days•

HRQoL outcomes*:
PGI-S score
MIDAS Total Score, Absenteeism Score, Presenteeism Score,Days of lost productivity Score
MSQoL Questionnaire (Total score, role function-preventive,role function-restrictive, emotional function domains)
EQ-5D Score

•
•
•
•
•
•

Safety and discontinuation outcomes:
AEs due to any cause
SAEs due to any cause
Discontinuation due to any cause
Discontinuation due to AEs
Discontinuation due to lack of efficacy

•
•
•
•

Exclusion

30

Exclusion•
Phase I clinical trials•
Case-control studies, case reports anddatabase analyses•
Methodology studies or protocols•
Pharmaco-economic studies•
Pharmacokinetics, Pharmacodynamics•
Reviews, letter, report, expert opinion•
Genetics studies•
Biomarkers studies•
Observational studies•
Guidelines•
SLR, meta-analyses and NMA †ACE – Angiotensin-converting enzyme; AEs – Adverse events; ARB – Angiotensin II receptor blocker; CGRP – Calcitonin gene-related peptide; MIDAS –Migraine Disability Assessment Test; MSQoL – Migraine-Specific Quality of Life; NMA – Network meta-analysis; PGI-S – Patient Global
Impression of Severity; RCT – Randomised Controlled Trial; SAEs – Serious adverse events; SLR – Systematic literature review*All time-points were of interest in the SLR, however, if outcome data was reported more frequently than monthly, data was extracted on a monthly
basis into the data extraction form. For instance, if a study reported outcome data at 4, 12 and 18 weeks, all data was extracted. However, if astudy reported outcome data at 4, 6, 8, 10 and 12 weeks, only the data at 4, 8 and 12 weeks was extracted.
†Reviews and meta-analyses are excluded from data extraction since aggregated results cannot be used in our analysis. However, good quality metaanalysis and systematic reviews will be used for crosschecking of references.
STUDY DESIGN

Criteria
Abstract & fulltext selection

Inclusion•
Phase II, III, IV randomised controlled trials•(Crossover up to time of crossover)•Conference abstracts from 2017-current•
Language English and Japanese (other languages will be
excluded)31

表 3-3 Study selection criteria f or observational studies

TREATMENT/INTERVENTIONPOPULATION

Criteria
Inclusion
Exclusion
Abstract selection•
Adult (18+) patients (males and females)•
Pediatric populations will be excluded
suffering from migraine.
•
Patients may suffer from either episodic or
chronic forms of migraine with or without
other additional headache conditions, such as
cluster headache
Full-text selection•
Adult (18+) patients (males and females)
suffering from migraine.
•
Patients may suffer from either episodic or
chronic forms of migraine; or from otheradditional headache conditions, such as
cluster headache.
Abstract & full•
All preventive pharmacological interventions•
Acute therapies not concomitant to any
text selection
for the treatment of migraine relevant topreventive therapies•
Non-invasive therapies (e.g. physical therapy)
Japan, including:•
Antiepileptic drugs (Valproic acid, topiramate,•
Alternative therapies (e.g. Chinese herbs)
gabapentin, levetiracetam)•
Devices•
Beta-blockers (Atenolol, metoprolol, nadolol,
propranolol)•
Antidepressants (Amitriptyline)•
Calcium channel blockers (Verapamil,
lomerizine)•
ARB/ACE inhibitors (Lisinopril, candesartan)•
CGRP receptor antagonists (Erenumab,
galcanezumab, fremanezumab)
Others (Botulinum toxin type A, magnesium•
preparation, tizanidine)32

OUTCOMESCOMPARATOR

Criteria
Abstract & fulltext selection

Abstract selection

Inclusion
Exclusion•
Interventions above compared to each other,•If multiple arms in RCT, at least two arms needor to placebo
to be of interest (for example, a 3-arm RCT
comparing acute vs. preventive vs. placebo will
be included whilst only data from thepreventive and placebo arm are of interest.)•

No selection on outcomes•

No selection on outcomes33

Criteria
Inclusion
Exclusion
Full-text selection•
Efficacy outcomes:•
Any outcomes not listed under inclusion•
Monthly Migraine Headache Days*•
Monthly Headache Days*•
Monthly Migraine Headache Attacks*•Monthly Headache Attacks*•Monthly use of acute migraine treatment*•
50% Reduction in Monthly Migraine Headache
days•
75% Reduction in Monthly Migraine Headachedays•
100% Reduction in Monthly Migraine
Headache days•

HRQoL outcomes*:
PGI-S score
MIDAS Total Score, Absenteeism Score,
Presenteeism Score, Days of lost productivity
Score
MSQoL Questionnaire (Total score, role
function-preventive, role function-restrictive,
emotional function domains)
EQ-5D Score

•
•
•
•
•
•

Safety and discontinuation outcomesAEs due to any cause
SAEs due to any cause
Discontinuation due to any cause
Discontinuation due to AEs
Discontinuation due to lack of efficacy

•
•
•

•

34

GEOGRAPHICLOCATIONSTUDY DESIGN

Criteria
Abstract & fulltext selection

Abstract & fulltext selection

Inclusion•
Observational studies•
Conference abstracts from 2017-current•
Language English and Japanese (otherlanguages will be excluded)

•

Japan

Exclusion•
Phase I-III clinical trials•
Case-control studies and case reports•
Methodology studies or protocols•
Pharmaco-economic studies•
Pharmacokinetics, Pharmacodynamics•
Reviews, letter, report, expert opinion•
Genetics studies•
Biomarkers studies•
Guidelines•
SLR, meta-analyses and NMA †•Any country not listed under inclusion

ACE – Angiotensin-converting enzyme; AEs – Adverse events; ARB – Angiotensin II receptor blocker; CGRP – Calcitonin gene-related peptide;
MIDAS – Migraine Disability Assessment Test; MSQoL – Migraine-Specific Quality of Life; NMA – Network meta-analysis; PGI-S – Patient
Global Impression of Severity; RCT – Randomised Controlled Trial; SAEs – Serious adverse events; SLR – Systematic literature review*All time-points were of interest in the SLR, however, if outcome data was reported more frequently than monthly, data was extracted on amonthly basis into the data extraction form. For instance, if a study reported outcome data at 4, 12 and 18 weeks, all data was extracted.
However, if a study reported outcome data at 4, 6, 8, 10 and 12 weeks, only the data at 4, 8 and 12 weeks was extracted.
†Reviews and meta-analyses are excluded from data extraction since aggregated results cannot be used in our analysis. However, good quality
meta-analysis and systematic reviews will be used for crosschecking of references.

35

3.2.2 使用したデータベース
使用したデータベースを以下に示す。
海外の文献データベース：• MEDLINE• MEDLINE In-Process & Other Non-Indexed Citations• EMBASE• CENTRAL (note: search performed for RCTs only, CENTRAL was not in scopefor Observational studies)• CDSR
日本の文献データベース：• 医中誌
海外の文献データベースの MEDLINE, EMBASE, CENTRAL, CDSR については Ovid を使用
し、検索は 2020 年の 2 月 21 日に実施された。国内のデータベースである医中誌については、
2020 年 3 月 12 日に検索を実施した。その後、分析枠組み決定後の 2021 年 10 月 29 日に双方をアップデートした。
下記の 2017 年以降の学会発表についても、Ovid に掲載されているものは前述の検索に含ま れていると想定し、Ovid に含まれていないものを追加的に検索した。検索は以下の関連サイト にア ク
セスして実施した。
• International Headache Society (IHS): 2017-current (2017-2018: search in
Ovid; 2019: hand search)• American Headache Society (AHS): 2017-current (search in Ovid)• European Academy of Neurology Congress (EANC): 2017-current (searchin Ovid)• American Academy of Neurology (AAN): 2017-current (search in Ovid)• The European Headache Federation (EHF): 2017-current (search in Ovid)• Japanese Headache Society (JHS; abstracts in Japanese): 2017-current(hand search)
また、下記の臨床試験データベースに対しても検索の対象とした。検索は以下の関連サイトにア ク
セスして実施した。
 Clinicaltrials.gov – US National institute of Health International Clinical Trials Registry Platform (ICTRP) – World HealthOrganization
 EU Clinical trials register (EUCTR) Japanese Medical Association Center for Clinical Trials (JMACCT) Clinical
Trial Registry
3.2.3 使用した検索式
検索式は、臨床試験（RCT）と観察研究のそれぞれに設定し、疾患（MeSH and text）、研究デザ
インおよび介入に対する用語を組み合わせた。MEDLINE および EMBASE での臨床試験の検索には、Cochrane で検証された手法を用いた。HTA ガイドラインに従って、検索はデータ ベース
ごとに実施した。検索式は Appendix 3-1a および 3-1b にそれぞれ記載した。
3.2.4 シ ステ マティックレビューの実施
2020 年から 2021 年にかけて実施した海外と国内の文献に対するシステマティックレビュ ーの概要を下記に記載する。
36

The methods used for the SLR are in line with the Cochrane collaboration 11 andPRISMA (Preferred Reporting Items in Systematic Review and Meta-Analysis 12).
The process for study selection was performed in two stages. The first stage
involved the review of the records title and abstract by two researchers against
the pre-determined eligibility criteria for PICOS. If exclusion of a record based on
its title/abstract was not possible, the full-text publication was retrieved andevaluated against the eligibility criteria in the second stage of screening. All
screening decisions were documented in Excel screening files. This second stage
was also performed by two researchers. When consensus was not achieved, an
independent quality controller was involved. The inclusion and exclusion process
was documented including reviewers’ initials, the reason for exclusion (ifapplicable), and additional comments on the decision.
Results:
In total, the literature search identified 4,420 records from bibliographic databases(3,703), trial registries (717), study tables from Eli Lilly trials (5), and key
publications that were retrieved through reference mining. In total, 195
publications relating to 100 individual trials were included for data extraction. A
flow diagram of the numbers of studies included and excluded at each stage of theselection process is provided in 図 3-1.

37

図 3-1 PRISMA flow chart of RCT studies38図 3-2 PRISMA flow chart of observational studies39図 3-1 においては、オレンジで 2021 年のアップデートの検索時における追加文献数を示している。緑で示した 5 つの研究は、システマティックレビューで同定された自社試験のうち論文に含まれていないデータを追加したものである。赤で示した 1 つの研究はプロトコルに規定のプロセスにより抽出したものである。
表 3-4 Number of Identified publications
Original
Update# of hits
searchSearchGalcanezumab
27
10
Valproic acid7
1
Propranolol
12
1
Lomerizine
0
0
Other
128
19
Total
164
31

Total
37
8
13
0
147
195

195 件の結果より、ガルカネズマブの７試験が同定された。このうち、CGAN（第Ⅱ相）、CGAW（ 第Ⅲ相）は日本人を対象としているが、定義された対象集団のデータが限定されているため、 海外の
第 3 相試験（CGAG/CGAH/CGAI）のデータを含めてメタアナリシス及び間接比較に使用した。 除外された 2 試験は、それぞれ反復性頭痛と慢性頭痛が分かれていない、用法用量が異な っていたという理由で除外された。
各試験の詳細なデータについては、3.5 章および 4 章に記載した。
表 3-5 同定した弊社主導の本剤の臨床研究(論文)の一覧
サンプル 対象患者
臨床試験名
介入
比較対照
Ref erence
サイズ
ART-01
Unspecif i Goadsby 2019 13
Galcanezumab Placebo 217
NCT01625988
ed
Dodick 2014 14
EM/0-2 Ayer 2018 15
CGAB
Galcanezumab Placebo 410
SOC
Skljarevski 2018 16
NCT02163993
f ailure Oakes 2018 17
CGAG
EM/0-2 Detke 2020 18(EVOLVE-1)
Galcanezumab Placebo 858
SOC
Stauf fer 2018 19
NCT02614183
f ailure Ford 2019 20
CGAH
EM/0-2
Skljarevski 2018 21(EVOLVE-2)
Galcanezumab Placebo 915
SOC
Ford 201920
NCT02614196
f ailure
CGAI
CM/0-2(REGAIN)
Galcanezumab Placebo 1113
SOC
Detke 2018 22
NCT02614261
f ailure
462
EM+CM/
CGAW(incl.
2-4 SOC Mulleners WM(CONQUER)
Galcanezumab Placebo Japanese f ailure2020 23
NCT03559257
patients
Reuter 2021 24
n=42)
459
EM/0-2 Sakai 2020 25
CGAN
Galcanezumab Placebo (Japanese SOC
Shibata 2020 26
NCT02959177
patients) f ailure
Tatsuoka 2021 27

40

プロプラノロールの RCT は 13 件報告されている。しかし、システマティックレビューで同定された試験にガルカネズ マブとの直接比較がなかったことと有効性のア ウトカムが異なっていたため、
PICOS の対象集団の条件を変更して abstract screening から再度実施した。図 3-3 のプロセスに従い、間接比較に最も適した研究を選択した。以下に詳細を記載する。
図 3-3 Selection process on propranolol studies

The majority of propranolol studies were performed in populations with unspecified
migraine (8), one trial included patients with chronic migraine, and one included
patients with episodic migraine. The relatively high proportion of patient
populations with unspecified migraine may, in part, be explained by the study
years. Six of the propranolol studies were conducted prior to the year 2000, while
the definition of chronic migraine was included only in the 2nd edition of theInternational Classification of Headache Disorders (ICDH-II), published in 2004.
Four studies compared propranolol with placebo; two, with topiramate; two, withnadolol; one, with amitriptyline; and one, with valproate. Selected studies for
propranolol are shown in 表 3-6.
表 3-6 Propranolol studies
AuthorTitle
Pradalier et al 1989
Long-acting propranolol in
migraine prophylaxis: resultsof a double-blind, placebocontrolled study.
Mathew et al 1981
Ryan et al 1984

Prophylaxis of Migraine andMixed Headache. A
Randomized Controlled Study
Comparative study of nadolol
and propranolol in prophylactic

Reference
Cephalalgia (1989) 9(4):247-53. 28

Headache (1981) 21(3):105-9. 29
American Heart Journal(1984) 108:1156. 30
41

Sargent et al 1985

Sudilovsky et al
1987
Diener et al 1996

Diener et al 2004*

Ashtari et al 2008

Jaf arpour et al 2016

Dakhale et al 2019

treatment of migraine
A comparison of naproxen
sodium to propranololhydrochloride and a placebo
control f or the prophylaxis of
migraine headache
Comparative efficacy of nadolol
and propranolol in the
management of migraine.
Cyclandelate in the prophylaxisof migraine: a randomized,
parallel, double-blind study incomparison with placebo andpropranolol.
Topiramate in migraine
prophylaxis Results f rom aplacebo-controlled trial with
propranolol as an active
controlA double-blind, randomized
trial of low-dose topiramate vspropranolol in migraine
prophylaxis
Ef f ect of a traditional syrup
f rom Citrus medica L. f ruitjuice on migraine headache: A
randomized double blind
placebo controlled clinical trial
Low-dose sodium valproate
versus low-dose propranolol inprophylaxis of common
migraine headache: A
randomized, prospective,
parallel, open-label study

Headache (1985) 25(6):320-324. 31

Headache (1987) 27(8):421-426. 32
Cephalalgia (1996) 16(6):441-7. 33

J Neurol (2004) 251:
943–950. 34

Acta Neurol Scand (2008)
118: 301–305. 35
Journal of
Ethnopharmacology(2016) 179: 170–176 36
Indian J. Pharmacol.
(2019) 51(4): 255-262 37*This paper was excluded from the main body NMA and SLR update due to the fact it enrolled adolescent patients (SLR
focused on adult patients with migraine defined as those aged ≥18 years), but due to the limited evidence base available
for propranolol, to support the identification of the best evidence base to conduct an ITC, Lilly re-introduced the paper as
a possible option for evidence selection to drive ITC versus propranolol.

In order to decide which propranolol data could be used to form the foundation for
the indirect treatment comparison analysis, Lilly identified most suitable evidence
as below. This evidence, as a pre-requisite needed to report the effectiveness ofpropranolol in prophylactic migraine based on input measures that drive the costeffectiveness model, namely the change from baseline in migraine headache days
and response rate.
As such, one of the minimum requirements for the evidence base for propranolol
are:• Report Mean Change from Baseline (CFB) in Migraine Headache Days. If
Migraine Headache Days was not available, consideration was given to consider
evidence reporting the mean CFB in Headache days (ie non-specific for
migraine) AND

42

•

Report Response Criteria. The CE model allocates the patient to a state of
response or non-response at 12 weeks. The clinically meaningful response inepisodic migraine is regarded as ≥50% reduction in monthly migraine
headache days and for chronic migraine the clinical meaningful response is set
at ≥30% reduction in monthly migraine headache days. Given these criteria,
as a minimum, in order to allocate patients by response state: responder or
non-responder, the evidence for propranolol needed to report at least the 50%
reduction in Migraine Headache days (or as a fall back the less specific 50%
reduction in Headache days).

Key Criteria Used to Inform Selection of Propranolol Evidence to Drive Indirect
Treatment Comparison (ITC):
In addition to the criteria on key effectiveness measures, Lilly identified other key
criteria in determining the best evidence for selection to inform the ITC (see 図 34).
1. Lilly strove to select a trial where the evidence was unbiased. The goal was
to select evidence based on double blind randomized controlled trials,
ideally multi-centre trials. Single centre trials can include a level of bias.
2. The evidence needed to be placebo controlled. We wanted to selectevidence that includes a common comparator as was included in the
Galcanezumab pivotal trials so an indirect comparison can be drawn basedon placebo adjustment.
3. In addition, ideally but not as a pre-requisite, we were looking to select a
study reflecting a robust sample of propranolol patients.
4. Then there were secondary criteria (i.e. Level 3 criteria), which were
influencing evidence selection including trying to identify evidence which isrepresentative of current migraine management in Japan. Lilly determined
age of study to represent a proxy of the likelihood the study was
representative of current prophylactic migraine management. Ideally, we
would want to select a study which evaluated propranolol at a dose as close
to as possible as the real world (RW) dose of propranolol used in Japan. In
the event, there was no study that reflected a dose close to RW propranolol
dose in Japan, the goal was to select a study with a dose higher than isused in Japan, so that the evidence would result in propranolol effectivenesshigher than what would be expected in Japan. It was important not to bias
the results against propranolol, favouring to select evidence based onhigher RW use which would expect to deliver the same or better efficacy
than the dose used in Japan in the Real World setting.
5. Finally, an ideal situation would be to select a study enrolling patients who
had failed 1 or more prior preventative treatments to more closely
represent patient archetype who are eligible for galcanezumab in the Japan
Real World setting according to the guidance of optimal use guideline inJapan. If a study focused purely on patients with 1 or 2 prior preventative
treatments was not available, the next best option was to include evidence
based on a mixed cohort including naïve and possibly patients with 1 ormore prior preventative failures. The least desired evidence was to include
a trial focused on migraine prophylaxis naïve patients as these patients arelikely to perform better on propranolol than those who would be treatedunder the Japan reimbursement criteria, with a risk of over inflating the
propranolol effect size.
43

Level 2 Criteria

Evidence needed toreport key clinicalend-points that drive
CE model- CFB in MHD @ 12
weeks
And
- ≥50% Reduction in
MHD from Baseline@ 12 weeks
CE model allocatespatient to a state of
response/non
response at 12
weeks.

CT Design Elements

Effectiveness End-points

Level 1 Criteria

Evidence base which is robust,
limiting bias and /or uncertainty- Double-blind randomized
clinical trials . If possible, avoid
including evidence from open
label designs- Placebo-controlled: need acommon comparator to the
Galcanezumab trials from whichto conduct the indirect comparison- Ideally multi -centre trials.
Single centre trials have inherent
bias- Robust sample of propranolol
patients

Criteria matching Japan
Setting

図 3-4 Decision criteria f or selecting propranolol evidence to inf orm the indirect
treatment comparison versus galcanezumab
Level 3 Criteria- Is the evidence
representative of migraine
management & treatment
patterns in 2021 (age ofstudy used to inform thiscriteria)-Does the trial include
patients fitting the JP
reimbursement criteria e.g.
failed 1 or 2 prior preventative
treatments- Is the propranolol dose
similar to RW Japan Dose

Based on the criteria above, 9 of the 10 published manuscripts including
propranolol evidence were rejected, leaving one manuscript selected as thefoundational evidence to drive the indirect treatment comparisons versus
propranolol. The selected manuscript still had limitations and was unable to satisfy
all criteria (discussed below), however it was able to satisfy the key criteria.
Rationale for the rejection of 9 of 10 available papers focused on evaluating
propranolol evidence in prophylactic management of migraine.
The only published evidence which assessed mean change in Migraine HeadacheDays was Diener et al 200434. Sargent et al 198531 did record mean change inheadache days which could have been used as a surrogate, however Sargent et al198531 did not record the proportion of patients who achieved a clinicallymeaningful response defined as ≥50% reduction in headache days at week 12.
This meant Lilly still could not leverage Sargent et al 1985 because there was no
ability to inform the % of patients meeting response/non-response at week 12
which is foundational to the architecture of the CE model (see 表 3-7).
The majority of other papers focused their effectiveness measure on reduction in
number of headache attacks or migraine headache attacks 29, 30, 32, 35, 36, 37.
Despite the possibility to consider evaluation of a different effectiveness measure,other limitations in the papers recording change in frequency of migraine headache
attacks or headache attacks rendered their evidence not suitable.
表 3-7 records the reasons why a specific trial was rejected.

44

表 3-7 Propranolol – Reason to exclude
Age of study

Diener, 200434 (Episodic Migraine) selected study -Pradalier, 1998 28 (Episodic Migraine)

Mathew, 198129

2004: Old but
possibly reflects
current day practice

Old study, patientsnot likely to reflect
existing treatment
patterns andpatient
management today
Study evaluatedpatients between
1976-1980: Due totime study will not
be reflective ofexisting treatment
patterns andpatient
management today

Ryan, 198430

Very old and notreflective of existingtreatment patterns

Sargent, 198531

Very old and notreflective of existingtreatment patterns

Sudilovsky 1987 32

Very old and notreflective of existingtreatment patterns

DesignMulticentre

Placebocontrolled

Crossover

Entry Criteria(focused on #MHD/attacks toenroll in the study)

Enrolled Population
Mixed Population:
Migraine naïve andindication that somepatients had priortreatment as theirpreventative
medication was noted
as being withdrawn
during the wash out
periodRandomized DoubleBlind

Yes

Yes

No

Subjects with 3 to 12
migraine headaches(periods) and no morethan 15 headache days
Propranolol arm: Mean
6.1 migraine headachedays per monthRandomized DoubleBlind

Yes

Yes

No

8 Attacks/Month

Unclear if patients hadreceived priorpreventative
treatment

No

Nonspecific and does
not indicate the #MHDs to qualify to beenrolled: Patients with
migraine and patientswith mixed migraine
and muscle contraction
headache wererandomly allocated.

Not recorded if
patients had received
prior preventative
therapyNominimum of 3 migraine
attacks/monthNo

an average of 12
migraine headachedays over at least six
migraine attacks in the
3 months prior to entry
into the study

Probably a mixed
population as thewash-out phaseallowed for the washout of previous
medication

Randomized DoubleBlind

Randomized DoubleBlind

Randomized, parallel,
double-Blind

Randomized DoubleBlind

No

Yes

Yes

Yes

No

No

Yes

No

No

At least 3 Migraine
attacks per month

UnclearUnclear: patientswere deemed torequire preventative
medication, but nomention patients hadreceived priorpreventative45

medication

Ashtari 200835

Jafarpour 2016 36

Patients wereenrolled in 20032004 and results
published in 2008.
This study is old but
more likely to bereflective of todays
current treatment
pattern andmanagement

Recent study morereflective of current
treatment patterns
and patientmanagement

Randomized DoubleBlind

Randomized, parallel,
double-Blind

No

No

No
(Topiramate
notconsideredin Japan)

Yes

No

Frequency of three ormore migraine
headache attacks permonth during a 3month period before
entry

Mixed Population:
inclusion criteria
indicate: concomitantmigraine prophylactics
were withdrawn 1
month prior to entry
into this trial.

Yes

Clinical diagnosis of
migraine headache
without aura wereselected according to(ICHD-2) Inclusion
criteria: male or female
aged >18 years,
presence of ≥4
migraine attacks/monthin the absence of
medication overuse andnot due to any otherdisease, pain refractory
to preventive
medications, no current
prophylactic treatment
for migraine, no clinicalconditions that
precluded the use of
any of the drugs of thestudy.

Unclear but probably
a mixed population:
patients had to havemigraine prophylactics
withdrawn 1 monthprior to entry into thistrial.

46

Dakhale 201937

Very recent study
conducted between
2016-2017 where
the treatment
pattern and patientmanagement would
be consistent withcurrent practice

Diener 199633

Very old study:
Patients wereenrolled in the
study in Sept 1991April 1994 and thus
the treatment
pattern then is notreflective of todays
treatment pattern

A randomized,
prospective, parallel,
open-label study
Risk of bias due toopen-label design

Controlled, Double
blind

No

Patients with a historyof migraine withoutaura for at least 6months before
evaluation (as per ICHD
definition [2.1.1])
Patients experiencing
2–6 migraine
attacks/month, but not≥15 attacks/month

Migraine prophylactic
therapy-naive patients
who satisfied theselection criteria. The
population in thisstudy are notconsistent with thecriteria of the
population likely to beeligible forreimbursement for
Galcanezumab. The
results of propranolol
in this study are likely
to be overestimatedgiven the population
are naive to priorpreventative
therapies.

No

Patients with a migrainewith and/or withoutaura according to the
IHS criteria; migraine
history of at least 12
months duration; amean number of 2-10
migraine attacks permonth within the last 3
months prior to thestudy

Unclear patients onprior preventive
medication werewithdrawn within the
4-week run-in period

No

No

Yes

(Comparison
to sodium
valproate)

Yes

47

Age ofparticipants% Female

N ofpropranolol

Propranolol dose

Titration

Country participation

Diener, 2004 (Episodic Migraine)- selected study -34

14 - 66
years
Median 41
years

76-83%

143

160mg once daily: Mean dose

Yes: 8 weeks sopatient assessment
was based on
optimized dose

Pradalier,
Migraine)28

18-65 years

Propranolol: 77.5%

31160mg Long Acting once
daily

No

Multi-country(n=13):
Germany, Sweden, Spain,
Italy, Taiwan, South Africa,
Korea, UK, Australia,
Denmark, Finland, Franceand Netherlands
France1998

Mathew, 198129

Ryan, 198430

Sargent, 198531(Episodic

higher than RW Japanese
propranolol dose. Results inflated
in favour of propranolol due tohigher propranolol dose used

Mean dose higher than RW
Japanese propranolol dose.
Results inflated in favour of
propranolol due to higher
propranolol dose used

19-57 years

92.7%

44

20mg thrice daily: Mean dose
higher than RW Japanese
propranolol dose. Results inflated
in favour of propranolol due tohigher propranolol dose usedNo

Probably USA

21 - 60
Years

73%

16

160mg Once daily: Mean dose

No

USA

18-65 years

79%

44

40mg thrice daily: 120mg in
total. Dose lower than other

Patients weretitratrated up frompropranolol 40mg/2
daily in the 2 weekprior to randomization
to 40mg/ 3 times
daily
No

USA

No

Iran: Not likely to be
representative of a Japan
demographic

UnclearIndia: Not likely to be
representative of a Japan
demographic/Japan migraine
management

This cohort is nearly all
female and not
representative of aJapan demographic
where male suffers are
more frequent than
<10%

higher than RW Japanese
propranolol dose. Results inflated
in favour of propranolol due tohigher propranolol dose usedstudies but remains higher than
RW Japanese propranolol dose.
Results in favour of propranolol
due to higher propranolol doseused

Sudilovsky 198732

18-60 years

Propranolol arm:
77%

44

Ashtari 200835

18-65 years

Propranolol: 76.7%30

Jafarpour 201636>18 years

83%-88% female

26

80mg twice daily: Mean dose

higher than RW Japanese
propranolol dose. Results inflated
in favour of propranolol due tohigher propranolol dose used
80mg daily: Mean dose higher
than RW Japanese propranolol
dose. Results inflated in favour of
propranolol due to higher
propranolol dose used
20mg thrice daily: Trial
reflected a lower propranolol total
daily dose. The dose in this study
is still higher than mean
propranolol dose used in RW in
Japanese patients

USA

48

Dakhale 2019 37

Diener 199633

18-60 years

18-60 Years(mean age
39 across alltreatment
arms (+/-12
years))

Propranolol arm:
63% female(19/30)30

78% across alltreatment arms arefemale78
randomised,evaluable
patients on
propranolol
in ITT 68

Low dose 40mg SR oncedaily

Yes: dose up titration
to 40mg SR twice
daily was allowed
based on response

India: Not likely to be
representative of a Japan
demographic/Japan migraine
management

Propranolol 40mg threetimes daily (120mg total
daily dose): Mean dose higher

No

Germany

This study evaluated the lowest
propranolol dose of 40mg once
daily, which is more consistent
with the RW mean doseprescribed for propranolol inJapanese patients. Patients could
increase the dose to 40mg SR
twice daily if there was little to no
responsethan RW Japanese propranolol
dose. Results inflated in favour of
propranolol due to higher
propranolol dose used49

Timepoint (primary
endpoint)

Diener, 2004
(Episodic Migraine)- selected study -34
Pradalier, 199828(Episodic Migraine)

26 weeks (includes 8 weektitration): 18 weeks of double
blind treatment. As assessment>12 weeks optimized
propranolol efficacy
12 weeks

Mathew, 199829

12 weeks

Ryan, 198430

12 weeks

Sargent, 198531

12 weeks

Sudilovsky 198732

12 weeks

Ashtari 200835

8 weeks: Assessment at 8
weeks likely to suboptimize
propranolol efficacy biasing theresults in favour ofGalcanezumab. This was a key
factor in determining whether toselect this study to run indirect
treatment comparisons# of patients in
Propranolol Arm
completing thestudy/evaluable @ timeof primary end-point
102

Mean
change inmean MHD(availability)

Mean
Change inHD

30%
response
rate inMHD

50% response
rate in MHD

Monthly rescue
data recorded

Yes

Not needed as
CFB in MHD
availableNo

Yes: 50%
reduction inmean migraine
frequency

Yes: change inutilization of
rescue medication
captured

22 Completed: 31 patientswere randomized topropranolol 160mg after
the run period and 9
discontinued and thus were
not evaluable
38 completed the trial can
could be assessed for
effectiveness evaluations

No

No

No

No

Yes

No

No: Only have
improvementin average
weekly index

No

Rescue wasallowed but notrecorded

12: very very small cohort
with evaluable results. Risk
results not representativeof a general cohort treatedwith propranolol<44 patients: Authors
indicated that 20 patients
discountinued before 12
week assessment and thus
were not evaluable but did
not indicate which
treatment arm the patientswere discontinued
30

No

No

No

Average %improvement but
not the % who
achieved a 50%
improvement
No

No

Yes

No

No

Rescue wasallowed but notrecorded

No

No

No

Rescue wasallowed but notrecorded

29

No

No

No

Yes but only for
50% reduction inheadacheintensity
No

Rescue wasallowed but notrecordedUnclear50

Timepoint (primary
endpoint)

Jafarpour 201636

Dakhale 2019 37

Diener 199633

4 weeks: Assessment at 4
weeks likely to suboptimize
propranolol efficacy biasing theresults in favour ofGalcanezumab. This was a key
factor in determining whether toselect this study to run indirect
treatment comparisons
12 weeks

12 weeks# of patients in
Propranolol Arm
completing thestudy/evaluable @ timeof primary end-point
21: 5 patients wererecorded as having
discontinued on propranolol
leaving 21/26 withevaluable resultsMeanchange inmean MHD(availability)

Mean
Change inHD

30%
response
rate inMHD

50% response
rate in MHD

Monthly rescue
data recorded

No

No

No

No

Allowed to use
rescue medication
which may bias
the results

28: 2 patients discontinued
in the propranolol arm

No

No

No

Yes was recorded
but not recordedin the results

68

No

No

N0

No: trial
evaluated a 50%
reduction in
migraine attacks
but did notreport 50%
reduction in
migraineheadache days
No: trial
evaluated a 50%
reduction in
migraine attacks
but did notreport 50%
reduction in
migraineheadache days

Acute medication
was allowed for
migraine attacks
up to 12 days/
month. Post hoc
analysis which
demonstrated
propranolol was
not superior toplacebo when
rescue medication
was accounted forGreen boxes indicate that the trial fulfils the criteria, amber indicates that the criteria is fulfilled but with some limitations and red indicates that the criteria is not
fulfilled (see 図 3-4 Decision criteria for selecting propranolol evidence to inform the indirect treatment comparison versus galcanezumab).

51

表 3-8 同定したプロプラノロールの臨床研究（論文）の一覧表
比較対 サンプル
臨床試験名
介入
Ref erence
サイズ
照NCT00236561 Propranolol
Placebo 143
Diener (2004)34
以下に Diener et al.のみがプロプラノロールの臨床研究として同定された根拠を述べる。
1: Change in monthly migraine headache days•
With the exception of Diener 200434, none of the other publications included
mean change from baseline in Migraine Headache Days.
•
Sargent et al 1985 did evaluate reduction in headache days but unfortunately
did not report the proportion of patients who met the clinically meaningful
response criteria.
2： Response Criteria: Clinically Meaningful Response (≥30% reduction for episodic
migraine and ≥50% reduction for chronic migraine) at Week 12• Pradalier et al 198928, Mathew et al 198129, Ryan et al 198430 , Sargant et al198531, Diener et al 199633, Jafarpour et al 201636 did NOT record any data to
indicate the % of patients who met a clinically meaningful response whichmeant all these papers needed to be rejected as the CE model is driven by
allocation of patients by responder/non responder status at week 12.
• Ashtari et al 200835 and Jafarpour et al 201636 assessed effectiveness at week
8 and week 4 respectively. It is likely that the peak effectiveness of propranolol
is NOT reached at week 4 or 8 and thus both these trials would underestimate
the effect size for propranolol, biasing the ITC in favour of galcanezumab. On
this basis, both these trials were disregarded on the basis of the timing of theeffectiveness, plus other reasons below.
3: Robustness of Evidence: Double-blind, Randomized Placebo-controlled Trial;
Multi-centre• Dakhale et al 201937 did not meet the criteria for robustness of evidence.
Dakhale et al 201937 is an open label single centre study which is subject tosignificant bias.
• Mathew et al 198129, Ashtari 200835, Jafarpour et al 201636 were all singlecentre studies where there is a risk of bias.
• Mathew et al 198129, Ryan 1984 et al 30, Sudilovsky et al 198732, Ashtari 2008
et al 35 and Dakhale et al 201937 are NOT placebo controlled. There is nocommon comparator with the galcanezumab trials making it impossible toperform an indirect treatment comparison with propranolol.
4: Robustness of Evidence: Evaluable Propranolol Patient Cohort•
Many of the studies had very small evaluable propranolol cohorts. Smaller
cohorts are subject to the impact of heterogeneity factors based on enrolled
population. The goal was to select evidence with larger propranolol cohorts.
•
Diener et al 200434 enrolled 143 patients, and had 102 evaluable propranolol
patients at 12 weeks. So across all studies this was the largest of all evaluable
propranolol groups.
•
Lilly believes there is significant limitation in the following studies as a resultof very small number of evaluable propranolol patients.
 Ryan et al 198430: 12 evaluable propranolol patients
 Sudilovsky et al 198732: 30 evaluable propranolol patients Ashtari et al 200835: 29 evaluable propranolol patients Jafarpour et al 201636: 21 evaluable propranolol patients52 Dakhale et al 201937: 28 evaluable propranolol patients
5: Enrolled population
None of the published propranolol evidence focused enrolment on a population
who had 1 or 2 prior preventative failure medication.
The description of the population studied was not well recorded in the majorityof trials.
• In Diener et al 200434 we know that the population was a mix of naïve andpatients who had received prior preventative treatment as the study
indicated that current preventative medication was tapered during thewashout period.
• Dakhale et al 201937 specifically included migraine naive patients and is
not representative of the patient population eligible for galcanezumab inJapan. The results of this study would likely over estimate the effect ofpropranolol in a population who have 1 or 2 prior preventative treatments.
This is another reason to reject Dakhale et al 201937 as viable evidence.
6: Age of Study•
A possible limitation of the evidence is the age of the study. The older the
study, the less likely the study results would reflect prophylactic migraine
management currently.
•
For this reason Lilly felt studies that pre-dated 2000 may not reflectcurrent migraine practice28,29, 30, 32, 33.
Rationale for Selection of Diener et al 200434•
It was the only study that captured the mean change in Migraine Headache
Days.
•
It included a response criteria assessment at week 12: defined as at least a
50 % reduction in average monthly migraine frequency.
•
Study was robust: Double blind, randomized, multi-centre. It appears to be
the only multi-country study and included enrolment of Asian patients from
Taiwan and S Korea where the management of migraine is likely to be
representative of that in Japan.
•
The study had the largest number of propranolol evaluable patients: 102. Allother studies were much smaller.
•
8 week titration phase of propranolol dose ensured the effectivenessassessment of propranolol was optimized.
•
The study population was a mix of naïve and those who had been pre-treatedwith prior preventative therapies. This was the only study where we can becertain that some of the patients randomized to propranolol had received priorpreventative therapy and thus were somewhat reflective of the population
likely to be eligible for galcanezumab, ie failed 1 or 2 prior preventative
treatments.
Limitations of Diener et al 200434• Age of enrollees included adolescents. Cohort age range was 14-66 years witha median age of 46 years. Given the median age is 41 years, the number ofadolescents enrolled is likely to be low. It is possible that adolescents are
more likely to be migraine treatment naïve (not confirmed by paper) andpossibly may perform better on propranolol. The limitation of this study
including treatment naive adolescent’s is only likely to result in an effectivenessbias in the ITC in favour of propranolol.
53

•

•
•

Enrolled Population: Subjects with 3 to 12 migraine headaches (periods) andno more than 15 headache days. The mean monthly migraine headaches atbaseline in the propranolol group is 6.1 (SD 2.7). The eligibility forreimbursement of galcanezumab is at least 4 migraine headache days permonth. Given the mean monthly migraine headache days was 6.1, a minority
number of enrollees may have lower number headache days than 4 which
would be considered not eligible for galcanezumab. It is likely that patientswith less severe disease are more likely to achieve a 50% response rate as therequired CFB in reduction in headache days is lower and thus again favouring
the effectiveness of propranolol biasing any ITC results in favour of propranolol.
The study duration was 26 weeks, while for galcanezumab outcomesconsidered in the evidence synthesis were reported at month 3 disadvantaging
galcanezumab.
The maintenance dose of propranolol reported in Diener et al (2004)34 was
160mg/day with a median average daily dose for the core double-blind phase(titration and maintenance) of 129.6mg/day. The dosing of propranolol in
Diener et al (2004)34 is substantially higher than the Japanese mean average
dose of 21.56mg/day (JMDC 2021 (Appendix 4-1)). Thus, the effectiveness ofpropranolol applied in the model represents the upper end of the effectivenessthat would be expected in the Japanese real-life setting.

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]
該当なし
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]該当なし
3.5 既存データの再解析
3.2 で同定された以下の 5 つのガルカネズマブの試験（CGAG, CGAH, CGAW, CGAI, CGAN）の有効性の結果を、片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う部分集団、 及 び 3 剤
目の治療を中止した部分集団に対して、反復性頭痛（CGAG, CGAH, CGAW and CGAN）と慢性頭痛（CGAI and CGAW）の結果を分けて、12 週における平均片頭痛日数のベースラインか らの変化量について再解析した。
表 3-9 Episodic studies and source documents considered
Study name and acronym
Study acronym/
identifier
CGAG:
Evaluationof I5Q-MC-CGAG
Galcanezumab in the Prevention NCT02614183
of Episodic Migraine- the EVOLVE1 Study (Evolve-1)
CGAH:
Evaluationof I5Q-MC-CGAH
Galcanezumab in the Prevention NCT02614196
of Episodic Migraine- the EVOLVE2 Study (Evolve-2)
CGAW: A Study of Galcanezumab I5Q-MC-CGAW(LY2951742)
in Adults With NCT03559257
Treatment-ResistantMigraine(CONQUER)

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54

CGAN: A Randomized, DoubleBlind, Placebo-Controlled Study of
LY2951742 (Galcanezumab) inJapanese Patients with Episodic
Migraine

I5Q-JE-CGAN
NCT02959177

表 3-10 Chronic studies and source documents considered
Study name and acronym
Study acronym/
identifier
CGAI:
Evaluationof I5Q-MC-CGAI
Galcanezumab in the Prevention NCT02614261
of Chronic Migraine (Regain)
CGAW: A Study of Galcanezumab I5Q-MC-CGAW(LY2951742)
in Adults With NCT03559257
Treatment-ResistantMigraine(CONQUER)

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55

3.6 メタア ナリシスの詳細 [該当する場合のみ]
以下のガルカネズマブの 5 試験を対象として、Best Supportive Care を比較対象技術とした反復性
片頭痛と慢性片頭痛における（（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者お よび（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者の対象集団）12 週後の片頭痛日数の変化を有効性のアウトカムとしたメタアナリシスについて以下に記載する。
表 3-11 メタアナリシスに用いた試験

試験名

含まれる患者集団

介入：ガルカネズマブ

プラセボ

CGAN

反復性片頭痛〇〇CGAW

反復性片頭痛・慢性片頭痛

〇

〇

CGAG

反復性片頭痛〇CGAH

反復性片頭痛

〇
〇

CGAI

慢性片頭痛

〇

〇

〇

以下に分析の詳細を記載する。
3.6.1 Meta-analyses methods
For a continuous outcome, meta-analyses were conducted for the mean difference
using the inverse variance method for pooling and the DerSimonian-Laird method for
tau which is used for the random effect.
The heterogeneity between the studies on each direct treatment comparison wasassessed through the inconsistency parameter (I²) statistic and the p-value of the Qstatistic. The I² can be interpreted as the proportion of total variability attributed toheterogeneity rather than chance. The importance of the observed value of I² dependson (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity(for example, p-value from the chi-squared test, or a confidence interval for I2). As aguide, the parameter can be interpreted as follows (from the Cochrane handbook,section 9.5.2 (Higgins and Green, 2011 39)) is as follows:•
0% to 40%: might not be important.
•
30% to 60%: may represent moderate heterogeneity.
•
50% to 90%: may represent substantial heterogeneity.
•
75% to 100%: considerable heterogeneity.
The heterogeneity statistic Q, which follows a central chi-squared distribution with
degrees of freedom of the number of studies minus 1, was used. The test depends on
the number of studies and has a low power when few studies and a high power whenmany studies. Therefore, this p-value was interpreted with caution and in light of thenumber of studies included in the meta-analysis. In the absence of heterogeneity, theresults of fixed effects (FE) and random effects (RE) models are expected to be
identical. Between studies variance τau2, with 95% CI and p-value were reported.
3.6.2 Meta-analyses results
メタアナリシスの結果を以下に述べる。対象集団（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者および（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者の結果は、 それ ぞれ
表 3-12 および表 3-13 の通りである。専門組織に指定された感度分析のデータは、Appendix 3-2に示す。
表3-12 12 週における平均片頭痛日数のベースラインからの変化量： 片頭痛予防薬の3剤目 の治療を中止した反復性片頭痛患者- Galcanezumab 120mg vs BSC (Placebo)56

TrialComparison

CGAG

galca
120mg
vs. placebo

CGAH

Test
ControlN,N,
Mean(SD), Mean(SD),SE
SE

Mean Difference(95% CI)

CGAN
CGAW
Pooled data
FE Meta-analysis/Inverse/
RE Meta-analysis/Inverse/
tau2 /DL/
I2 [%]
Test ofheterogeneity: Q(df)
Test of funnel plot
asymmetry: t (df)DL - tau estimator: DerSimonian-Laird; FE: fixed effects; Inverse - pooling method:
Inverse variance weighting; linreg - weighted linear regression of the treatment
effect on its standard error; RE: random effects.

Source:¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Base.cas
e.em___tfls.rtf Table B.1.d

表 3-13 12 週における平均片頭痛日数のベースラインからの変化量：片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者- Galcanezumab 120mg vs BSC (Placebo)

Trial

Comparison

CGAI

galca
120mg
vs. placebo

CGAW

Test
N,
Mean(SD),SE

ControlN,
Mean(SD),SE

Mean Difference(95% CI)

Pooled data
FE Meta-analysis/Inverse/
RE Meta-analysis/Inverse/
tau2 /DL/
I2 [%]
Test ofheterogeneity: Q(df)
DL - tau estimator: DerSimonian-Laird; FE: fixed effects; Inverse - pooling method:57

Inverse variance weighting; RE: random effects.

Source:¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Base.cas
e.cm___tfls.rtf Table B.2.d

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]
システマティックレビューでガルカネズマブとプロプラノロールを直接比較する試験は同定されなか った
ため、以下のガルカネズマブの 5 試験およびプロプラノロールの 1 試験を対象として、プロプラノロ ール
を比較対象技術とした反復性片頭痛と慢性片頭痛における（（ａ）片頭痛予防薬の 2 剤目の治療又は 3剤目の治療を行う反復性片頭痛患者および（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療 を行う慢性片頭痛患者）12 週後の片頭痛日数の変化を有効性のアウトカムとした間接比較を実施した。 以
下に詳細を記載する。感度分析に用いたバルプロ酸のデータは Appendix 3-2 に示す。
表 3-14 間接比較に含まれる試験

試験名

含まれる患者集団

介入

比較対照技術CGAN

反復性片頭痛ガルカネズマブ

プラセボ

CGAW

反復性片頭痛・慢性片頭痛

プラセボ

CGAG

反復性片頭痛ガルカネズマブ
ガルカネズマブ

CGAH

反復性片頭痛ガルカネズマブ

CGAI

慢性片頭痛

ガルカネズマブ

プラセボ
プラセボ

Diener etal.34

反復性片頭痛・慢性片頭痛

プロプラノロール

プラセボ

プラセボ

以下に詳細を述べる。
3.7.1 Indirect comparison methods
The ITC is a statistical method used to pool results across a number of trials withcomparable patient populations linked by common comparators. The technique isbased on the assumption that, on a suitable scale, one can add and subtract thewithin-study estimates of relative treatment effects. For example, direct datacomparing treatment A with C and B with C can be used to indirectly compare A and
B. This is under the assumption that the following relationship between the estimatedtreatment effects holds: (A–B) = (A–C)–(B–C).
Frequentist adjusted indirect comparisons were conducted for each 2 by 2
comparisons, as described by Bucher et al 1997 40, using both fixed and random effects.
The fixed effect estimates were computed with the inverse variance approach for acontinuous outcome and the Mantel-Haenszel approach for a binary endpoint while
the random effects were calculated with the DerSimonian-Laird method. The basecase was the random effect model, given heterogeneity observed given limited sample
size of some studies due to post-hoc subgroup analyses, and differences in study
design/populations from comparator studies.
3.7.2 Software
The ITC analyses were performed using the Cheetah-tool (Indirect Comparison on
results from 2 Meta-Analyses version 1.1), a Lilly developed program based on
Qualified R version 3.4.4 package Meta. Treatment effects are estimated, following
the approach proposed by Bucher et al 199740.
3.7.3 Indirect comparison results58表 3-15 12 週における平均片頭痛日数のベースラインからの変化量：片頭痛予防薬の 2 剤目の治療
又は 3 剤目の治療を行う反復性片頭痛患者 - Galcanezumab 120mg vs Propranolol via
Placebo

Trial

Comparison

CGAG

galca
120mg
vs. placebo

CGAH

Test
ControlN,N,
Mean(SD), Mean(SD),SE
SE

Mean Difference(95% CI)

CGAN
CGAW
Pooled data
FE Meta-analysis/Inverse/
RE Meta-analysis/Inverse/
tau2 /DL/
I2 [%]
Test ofheterogeneity: Q(df)
Test of funnel plot
asymmetry: t (df)Diener et al.*
Propranolol vs.
placeboPooled data
FE Meta-analysis/Inverse/
RE Meta-analysis/Inverse/
tau2 /DL/
I2 [%]
Test ofheterogeneity: Q(df)
FE Indirect
galca
120mg
Comparisonvs. Propranolol
RE Indirect
galca
120mg
Comparisonvs. Propranolol
DL - tau estimator: DerSimonian-Laird; FE: fixed effects; Inverse - pooling method:
Inverse variance weighting; linreg - weighted linear regression of the treatment
effect on its standard error; RE: random effects.
* As Diener et al. reports only change in monthly (28-day) migraine f requency
averaged over the entire core double-blind phase (26 weeks) vs the f requency atbaseline, the outcome measure was used as the proxy of MHD change at week 12.

Source:¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Base.cas
e.em___tfls.rtf Table B.1.c59

表3-16 12 週における平均片頭痛日数のベースラインからの変化量： 片頭痛予防薬の2剤目 の治療
又は3剤目の治療を行う慢性片頭痛患者- Galcanezumab 120mg vs Propranolol via Placebo

Trial

Comparison

CGAI

galca
120mg
vs. placebo

CGAW

Test
ControlN,N,
Mean(SD), Mean(SD),SE
SE

Mean Difference(95% CI)

Pooled data
FE Meta-analysis/Inverse/
RE Meta-analysis/Inverse/
tau2 /DL/
I2 [%]
Test ofheterogeneity: Q(df)
Diener et al.*
Propranolol vs.
placeboPooled data
FE Meta-analysis/Inverse/
RE Meta-analysis/Inverse/
tau2 /DL/
I2 [%]
Test ofheterogeneity: Q(df)
FE Indirect
galca
120mg
Comparisonvs. Propranolol
RE Indirect
galca
120mg
Comparisonvs. Propranolol
DL - tau estimator: DerSimonian-Laird; FE: fixed effects; Inverse - pooling method:
Inverse variance weighting; RE: random effects.
* As Diener et al. reports only change in monthly (28-day) migraine f requency
averaged over the entire core double-blind phase (26 weeks) vs the f requency atbaseline, the outcome measure was used as the proxy of MHD change at week 12.
Source:¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Ba
se.case.cm___tfls.rtf Table B.2.c

3.8 追加的有用性の有無に関する評価
対象集団ごとに追加的有用性の有無に関する評価を下記に記載した。
表 3-17 追加的有用性の有無に関する評価のまとめ

60

対象集団

（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛
患者

介入

ガルカネズマブ

比較対照

プロプラノロール

アウトカム

12 週における平均片頭痛日数のベースラインからの変化量■ 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判断の根拠となったデ□ 前向きの比較観察研究 ■ RCT の間接比較ータ□ 単群試験の比較 □ 臨床データなし
追加的有用性の有無 ガルカネズマブ 120mg はプロプラノロールに比較して統計的に有意な差を
(
,
) P=
)
を判断した理由示した。 (mean dif ference:
追加的有用性の有無

対象集団（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性片頭痛患
者

介入

ガルカネズマブ

比較対照

プロプラノロール

アウトカム

12 週における平均片頭痛日数のベースラインからの変化量■ 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判断の根拠となったデ□ 前向きの比較観察研究 ■ RCT の間接比較ータ□ 単群試験の比較 □ 臨床データなし
追加的有用性の有無 ガルカネズマブ 120mg はプロプラノロールに比較して統計的に有意な差を
(
,
) P=
)
を判断した理由示した。(mean difference:
追加的有用性の有無

対象集団（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者

介入

ガルカネズマブ

比較対照Best Supportive Care (BSC)

アウトカム

12 週における平均片頭痛日数のベースラインからの変化量■ 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判断の根拠となったデ□ 前向きの比較観察研究 □ RCT の間接比較ータ□ 単群試験の比較 □ 臨床データなし
追加的有用性の有無 ガルカネズマブ 120mg は BSC に比較して統計的に有意な差を示した。
(mean dif ference:(,)P)
を判断した理由
追加的有用性の有無

対象集団（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者

61

介入

ガルカネズマブ

比較対照Best Supportive Care (BSC)

アウトカム

12 週における平均片頭痛日数のベースラインからの変化量■ 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判断の根拠となったデ□ 前向きの比較観察研究 □ RCT の間接比較ータ□ 単群試験の比較 □ 臨床データなし
追加的有用性の有無 ガルカネズマブ 120mg は BSC に比較して統計的に有意な差を示した。
を判断した理由(mean dif ference:(,)P)
追加的有用性の有無

62

4. 分析方法の詳細
4.1 分析方法
本分析はガルカネズマブとプロプラノロールまたは Best supportive care の治療の費用対効果を評価するためセミマルコフモデルにより費用対効果分析を実施した。マルコフモデルの健康状態は、①3ヵ月目の反応評価前の治療中、②反応評価後の治療中（4 ヵ月目以降）、③治療中止、④死亡の 4
つからなり、それぞれの健康状態は、月あたりの片頭痛日数と関連して設定されている。それぞれガル
カネズマブ、プロプラノロール、best supportive care の治療開始時に「①3 ヵ月目の反応評価前の治療中」となり、その 3 か月間後に、治療への反応性をもとに responder または non-responder に分類し（response assessment）、responder はその後それぞれの治療を継続するが（「②反応評
価後の治療中（4 ヵ月目以降）」への移行）、non-responder は「③治療中止」に移行する（図 4-1 参照）。その後は 1 ヵ月サイクルで健康状態が移行する。Response assessment 前後いずれにおいても、有害事象等を想定した所定の割合に応じ「③治療中止」に移行する。いずれの状態からも、国民の標準死亡率に従い死亡する。また、Distribution approach 41を用い、費用と QALY それぞれが持つ非線形な関係性をモデル化した。以下に詳細を述べる。本章ではバルプロ酸に関する感度分析に用いたパラメータも併せて記載する。
4.1.1 費用対効果の算出方法
The economic model has a semi-Markov model structure comprised of four healthstates; on-treatment prior to response assessment at month 3, on-treatment after
response assessment (4-month onwards), off-treatment and death (図 4-1). The
model has an assessment period (month 1 to 3) and post-assessment period (aftermonth 3). Each of the health states is associated with a mean monthly migraine
headache day frequency, and the response assessment period allows fordifferentiation between responders and non-responders.
Clinical parameters were derived from the subgroup of episodic or chronic migraine
patients that had a history of 1 or 2 prior preventive treatment failures (ie. 2nd or 3rdline preventive treatment), exactly 1 preventive treatment failures (ie. 2nd line
preventive treatment), exactly 2 prior preventive treatment failures (ie. 3rd line
preventive treatment) or at least 3 prior preventive treatment failures (ie. at least 4thline of preventive treatment) from the galcanezumab clinical trial program.
•
Responder and non-responder mean change from baseline in the monthly numberof migraine headache days at month 3 (‘responder criterion’, BSC comparison
only) – pooled galcanezumab clinical trial data•
Mean change from baseline in the monthly number of migraine headache days(‘combined criterion’, propranolol or valproic acid) Galcanezumab and propranolol - Indirect treatment comparison separately for
episodic and chronic migraine Galcanezumab and valproic acid - Indirect treatment comparison separately
for episodic and chronic migraine•
Proportion of patients responding to galcanezumab, BSC, propranolol or valproic
acid at month 3 (response rate) Galcanezumab and BSC, EM – ≥ 50% response rate - pooled galcanezumab
clinical trial data (episodic migraine only) Galcanezumab and BSC, CM – ≥ 30% response rate - pooled galcanezumab
clinical trial data (chronic migraine only) Propranolol - Indirect treatment comparison separately for episodic andchronic migraine Valproic acid – real world database analysis on patients remaining on
treatment at month 3 (JMDC 2021 (Appendix 4-1))
At the start of the model patients initiate treatment and after 3 months are assessed
for response in line with the galcanezumab Package Insert1 and Optimal Use
Guideline10.

63

①Assessment period (month 1 to 3)
Pooled galcanezumab clinical trial data were used to inform the proportion of episodic
and chronic migraine patients who met a 50% or greater reduction from baseline inmonthly migraine headache days (episodic migraine only) or a 30% or greater
reduction from baseline in monthly migraine headache days (chronic migraine only).
The assessment response rate chosen to apply to the separate populations areclinically meaningful endpoints for the prevention of migraine 42,43. As such, these areapplied as appropriate treatment continuation rules in the model.
• Patients who do not achieve a response at 3 months: will transition to the offtreatment health state where they have the mean change in monthly migraine
headache days of a non-responder and return to baseline monthly migraine
headache days over time. Those patients will only incur costs of BSC andbaseline utility associated with the respective migraine headache day value forthe remainder of the time horizon.
• For patients in the BSC arm who respond to treatment, they are assumed toremain on-treatment and maintain their responder mean migraine headache
day change and return to baseline monthly migraine headache days over 12months. This assumption is aligned with the NICE committee’s preferredassumptions from the NICE technology appraisal for fremanezumab 44 andgalcanezumab 45.
• For galcanezumab patients who respond to treatment: assumed to remain ontreatment and maintain their responder mean migraine headache day change
and only return to baseline monthly migraine headache days over time if they
discontinue treatment for any reason.
• For propranolol or valproic acid patients who respond to treatment: assumed
to remain on-treatment and maintain their responder mean migraine headache
day change and only return to baseline monthly migraine headache days over
24 months based on a persistency analysis conducted in JMDC database (JMDC
2021 (Appendix 4-1)).
The 3-month assessment period is informed directly from the double-blind treatment
period of the galcanezumab clinical trial program.
Episodic and chronic migraine patients treated with galcanezumab can discontinue forany reason during the assessment period. The discontinuation rate due to all-cause
prior to assessment of response (first 3 months of model) is aligned with the doubleblind treatment period of the galcanezumab clinical trial program. The discontinuation
rate is applied as a one-off discontinuation probability at the end of the assessment
period. The galcanezumab patients who discontinue go to the off-treatment healthstate and are assumed to rebound to the baseline monthly migraine headache days
over a waning period attributed to galcanezumab. For galcanezumab, this was basedon the observed migraine headache days during the washout period of the pivotal
clinical trials (CGAH for episodic migraine; CGAI for chronic migraine; see Section
4.2.1). The discontinuation rate for patients on BSC is assumed to be zero. No
additional discontinuation rate is assumed for propranolol or valproic acid to avoid
double counting, in particular in the post-assessment period.
②Post-assessment period (after month 3)• BSC comparison - For the BSC comparison, change from baseline in monthly
migraine headache days was analysed by responder status using pooled
galcanezumab clinical trial data, which allowed to model the mean reduction inmonthly migraine headache days for responders and non-responders
separately (‘responder criterion’).

64

Propranolol or valproic acid comparison - The reduction in monthly migraine
headache days stratified by responder and non-responder status was notavailable for propranolol or valproic acid; therefore, the combined (responder
and non-responder) mean change in monthly migraine headache days wasapplied for the comparison to propranolol or valproic acid in patients withepisodic or chronic migraine (“combined criteria”).
The change from baseline was applied to the baseline population specific to monthly
migraine headache days. The monthly migraine headache days is limited in the model
between the bounds of 0 and 30, based on the number of days in a treatment cyclefrom the galcanezumab trials. The mean change from baseline in monthly migraine
headache days was applied to each health state in the model and used in the
distribution to calculate the number of patients experiencing each frequency of
migraine headache days. The responder criteria were defined as the mean change inmonthly migraine headache days for responders and non-responders separately,
defined either by a 30% (CM) or 50% (EM) mean reduction in monthly migraine
headache days from baseline; the combined criteria were defined as responder andnon-responder mean change in monthly migraine headache days combined.
Beyond the trial data, the mean change in monthly migraine headache days forresponders who remain on treatment after the response assessment at month 3 wasassumed to remain constant until the end of the modelled time horizon for
galcanezumab. Patients who discontinued galcanezumab treatment, returned back tobaseline over 13 cycles. The stable effect on reduction in migraine headache days overtime was supported by long-term follow-up data from CGAI (CM), CGAJ, and therecently published 5-year open-label results of erenumab (EM) 46. In addition, thisassumption was aligned with other economic models in the preventive treatment of
migraine44,47.
•③Discontinuation due to any reason is a key transition point in the post assessment
period, thus a second discontinuation due to any reason was included for thosepatients who respond to treatment at month 3. For galcanezumab, these values havebeen taken from the pooled open-label studies CGAP and CGAJ to reflect the longterm discontinuation in the model and are applied at a per cycle (i.e. ‘month’)probability for the duration of the post assessment period in the model. When patients
discontinue treatment, they are also assumed to rebound to the baseline monthly
migraine headache days in the base case and the same waning assumptions apply as
for those patients who discontinued during the assessment period. Patients will incur
costs of BSC and baseline utility associated with the corresponding migraine headache
day value at baseline. The discontinuation rate for patients on BSC is assumed to be
zero in the post assessment period. No separate discontinuation rate is captured forpropranolol and valproic acid in the post-assessment period to avoid double counting.
Patients on valproic acid and propranolol stop treatment in line with the performed
persistency analysis on those treatments in the JMDC database.
④Patients could die from any health state and had an equal risk of death in all healthstates based on life tables of the Japanese general population (i.e. no excess mortality
was assumed).

65

図 4-1 Model structure

Distribution approach
The model includes a second structure, whereby the mean change in monthly migraine
headache days in each health state are used to estimate the number of patients
experiencing each frequency of monthly migraine headache days. This is achieved by
employing a statistical distribution (see Section 4.2.1) to estimate the full range ofmonthly migraine headache days from the mean monthly migraine headache days.
Based on the assessment of appropriate distributions, the model includes two different
distributions, the beta binomial and the negative binomial, and different distributions
are applied to the model populations in the base case:• Episodic migraine: Negative binomial distribution (base case), betabinomial distribution (scenario analysis)• Chronic migraine: Beta binomial distribution (base case), negative binomial
distribution (scenario analysis)
The choice of distribution was based on goodness-of-fit analyses.
Since the mean change in monthly migraine headache days does not capture the f ullrange and distribution around the mean of individual monthly migraine headache day
f requencies, this second aspect captures the non-linear impact on costs and QALYs
due to the f luctuating nature of disease (month-to-month variation of migraine
headache days experienced by patients). The number of patients experiencing eachf requency of monthly migraine headache days is used to calculate the costs and QALYs.
While migraine severity is an important patient outcome and has an impact onpatient’s HRQoL, adding migraine severity as an additional clinical outcome tomigraine headache day frequency would considerably increase the model complexity
and there is a lack of data to inform the granularity that would be required toincorporate severity within the current health states of the model, particularly to
combine with the current individual migraine headache days distribution structure.
Severity is also difficult to capture accurately as it is a subjective measure and differsfrom person to person. Furthermore, it was not deemed feasible to synthesis suchclinical inputs indirectly for active comparators (i.e. propranolol or valproic acid) given
the lack of evidence identified in the SLR.

66

Each of the health states is associated with a mean change in monthly migraine
headache days based on the change f rom baseline in monthly migraine headache daysf rom the galcanezumab clinical trial program (see Section 4.2.1).
表 4-1 provides a summary overview of the key model characteristics.
表 4-1 Model characteristics
Component
Description
Modelling
approachSemi-Markov model

Perspective

Japanese public healthcare
payer

Cycle length

Monthly (30 days)

Time horizon
Outcomemeasures
Discount rate
(costs)Discount rate
(benef its)

25 years (lif etime)

Sources of utility

QALYs (base case)
2.0% per annum
2.0% per annum

Patient-level MSQ v.2.1
data f rom CGAN, CGAG,
CGAH, CGAI and CGAW
(f or patients with historyof 1 or 2 prior treatments
or at least 3 priorpreventive treatments)
mapped onto EQ-5D-3l
utility scores using an
existing mapping f unction

Justification
Based on a review of literature andearly scientif ic advice relating to a
Markov model grouping categoriesof migraine headache days as
employed in the Botulinum toxin A
model 48 being too complicatedC2H 2019 49
Cycle length is chosen to matchthe monthly duration in the Phase
3 trials as well as the Phase 2
Japaneseclinicaltrialofgalcanezumab
C2H, 201949
C2H, 201949
C2H, 201949
C2H, 201949
While EQ-5D is generally thepref erred measure
by
HTA
jurisdictions, only CGAW collected
EQ-5D data. The EQ-5D was
administered at baseline and once
again at 3 months at the end of
the double-blind study period of
CGAW. The recall period of “today”
isparticularly
insuf f icient inmigraine as the EQ-5D was
administered during the study
visit and patients experiencing amigraine would have been unlikely
to attend a study visit in person.
Thus, the f ull impact of migraine
on HRQoL may not have been
captured when using the EQ-5D.
In
comparison,theMSQ
questionnaire, which was collected
in all Phase 3 trials as well as theJapaneseclinicaltrial,
wasadministered monthly throughout
the randomised and open-labelphases of the trials and has a 4week recall period. Theref ore, theMSQ instrument was able to better

67

capture more granular changes inhealth-related
qualityof lif ecompared to EQ-5D-5L.
Sources of drugcosts

NHI drug list

C2H, 201949

Sources of othercosts

Instruction on medicalcare f ee points (April
2021)

C2H, 201949

Resource use,
acute medicationuse

Trial-specif ic data f oracute medication use

Resource use,
direct health care

Published Japanese data
by Kikui et al. 50

Mortality

Normal population-levelmortality 51

Half -cycle
correction applied

No

Provided the granularity of use as
it applied to each Migraine
Headache Days f or which costs
could be applied toProvided Japanese local healthcare resource use associated with
migraine based on the Japanese
National Health and Wellness
SurveyA literature review was conducted
to assess whether migraine isassociated with an increased riskof death. However, no clear
evidence was identif ied to support
an excess mortality beyond thenormal population-level mortality
due to migraine.
The cycle length (one month) is
considered to be suf f iciently short
so that half -cycle corrections do
not
need
to
be
applied.
Furthermore, it has been argued
that half -cycle corrections do not
af f ect estimated incremental costs
and benef its and may theref ore
not be needed in economic
evaluations 52

4.1.2 モ デルで使用した仮定
モデルおよび費用対効果算出のための分析における仮定には、２つの key assumptions が存在し、それに基づき、シナリオ分析を実施した。使用した仮定を以下に述べる。
The first key assumption is the use of a negative binomial or beta-binomial
distribution and validity of the regression model used to estimate the dispersion
parameter, respectively intra-correlation coefficient. This approach assumes
that the entire treatment effect is captured through migraine headache days.
This is a required assumption to accurately model the effect of comparator
treatments and is tested by testing an alternative distribution.
• Another key assumption of the model pertains to the extrapolation of the
migraine headache days after the trial data, the base case assumes that it issustained from the point of assessment of response until the end of the time
horizon.
The model made several other assumptions, which are outlined in 表 4-2.

•

68

表 4-2 Summary of assumptions applied in the economic model
Assumptions
Justification
The model utilised monthly cycles (30 days) over which transitions are modelled andcosts and outcomes accrued. This is both convenient f or modelling the treatment
Cycle length
regimens and appropriate given the treatment cycle of galcanezumab and the trial
def inition of migraine headache days per month applied in the Phase 2 and Phase 3
RCT programme of galcanezumab.
The galcanezumab Package Insert and the Optimised used guidelines (OUGL) statethat doctors should review treatment af ter 3 months and continue if patients benef it
f rom it. To ref lect these criteria in the model, change f rom baseline in monthly
Responder, non-responder migraine
migraine headache days was analysed by responder status applying the clinicalheadache days derived separately based
meaningf ul response criteria of 30% or 50% or greater reduction in migraineon galcanezumab trials and applied toheadache days f or CM, respectively EM patients. This allows to model the mean
the galcanezumab and BSC arms of the
reduction in monthly migraine headache days f or responders and non-responders
model.
separately. This analysis is only considered f or the comparison to BSC, f or which
individual patient level data are available f rom the galcanezumab clinical trial
program.
A combined criterion was applied to non- Since no publicly available inf ormation by responder/non-responder status could be
responder and responder mean change
identif ied in the SLR, the mean dif f erence derived f rom the ITC is applied f or the
migraine headache days tomean change f rom baseline in monthly migraine headache days f or propranolol andgalcanezumab when compared tovalproic acid.
propranolol or valproic acid69

Treatment responders on galcanezumab
remain on treatment and are assumed tomaintain response, or combined meanchange migraine headache days, until
the end of the time horizon and only
stop treatment f or all-cause
discontinuation

Patients who discontinue active
treatment due to non-response or lack ofpersistency (valproic acid or propranolol)
or all-cause discontinuation(galcanezumab) switch to BSC treatment
only and revert to baseline monthly
migraine headache days f or theremainder of the time horizon
Patients who discontinue active
treatment are assumed to wane back tobaseline monthly migraine headachedays at dif f erent rates based on available
data f or the respective modelledtreatments

Ef f icacy data f or galcanezumab are available f or up to one year. Results f rom CGAP
and CGAJ, the 12-month open-label saf ety studies in patients with episodic or
chronic migraine support galcanezumab’ durability of ef f ect f or up to a year 53, 54. A
decrease in the number of monthly migraine headache days was observed at month
1 (decreases of 4.5 days f or the 120 mg dose, with an initial 240mg dose f or the f irst
month), with plateauing of ef f ect several months later and maintenance of ef f ect
throughout 12 months (with decreases of 6.4 days at Month 1253). Data f rom the 9month, open-label extension phase of CGAI in patients with chronic migraine
indicated that reductions in migraine headache days during the 3 –month double
blind period were sustained during the OLE phase, and the percentages of patientswith clinically meaningf ul reductions in migraine headache days increased f rom therates observed in the double-blind period 55,56. The f indings f rom galcanezumab
open-label extensions is f urther supported by the 5 year open label extension data of
erenumab in episodic migraine, which showed a continuous ef f ect of erenumab atyear 546.
Galcanezumab or CGRP concentrations were similar when compared across various
ADA titre categories suggesting that ADA has no appreciable ef f ect on the PK of
galcanezumab nor does it interf ere with the binding of the CGRP ligand to thegalcanezumab antibody55. Consequently, no treatment waning is expected while ontreatment.
This assumption is consistent with the NICE committee’s conclusions f or theappraisals of erenumab47, f remanezumab44 and galcanezumab45.

The waning period attributed to each modelled active treatment is inf ormed by theobserved migraine headache days during the washout period of the pivotal clinical
trials (CGAH f or EM and CM; CGAI f or scenario analysis). No such washout data wasavailable f or propranolol or valproic acid. Given the lack of washout period data andthat propranolol and valproic acid are daily orals it is assumed that the half -lif e cycleof the treatment is very short. Theref ore, similar to BSC, patients on valproic acidand propranolol return to baseline migraine headache days immediately af ter they70

discontinued treatment.

There is no placebo response modelled.
BSC responder, non-responders
discontinue treatment af ter theassessment period at dif f erent rates
back the baseline monthly migraine
headache days. Non-responders,
immediately in the next cycle.
Responders, wane back over 12 months

No excess mortality in the model

Discontinuation is captured through theassessment of response and due to allcause (galcanezumab) and persistency
f or propranolol and valproic acid.

Placebo arms f rom the trial assumed asa proxy f or BSC in the model

Aligned with the NICE committee’s pref erred assumptions f rom the NICE technology
appraisal f or f remanezumab and galcanezumab, responders in the BSC arm in themodel return back to baseline migraine headache days at 12 months44,45.

Given conf licting evidence in the literature regarding migraine-specif ic mortality, no
excess mortality was considered in the model (Gudmundsson et al, 2010 57; Asberg
et al, 2016 58). Theref ore, patients f rom the on-treatment and of f -treatment healthstate had an equal probability of transitioning to the health state ‘death’. The
background mortality risk does not dif f er by treatment.
This is also consistent with past NICE technology appraisals in migraine44,45,47,48.
The proportion of patients being persistent to propranolol or valproic acid treatment
in Japan was based on a local Japanese claims analysis. (JMDC 2021 (Appendix 41)). For galcanezumab, no longterm data f rom routine clinical-practice are available.
Hence an all-cause discontinuation rate was considered to align with the persistency
analysis f or propranolol and valproic acid since reasons f or non-persistence is notknown. No additional discontinuation rate was considered f or propranolol or valproicacid.
It is assumed appropriate that the placebo arm in the randomised controlled trials of
galcanezumab is representative of best supportive care in patients who experienced
either 1 or 2 or at least 3 prior preventive treatment f ailures.
Patients in the placebo group of the clinical trials were allowed acute medication to
manage their symptoms.

71

25-year lif etime horizon

Treatment – specif ic utility values

Given that migraine is a chronic disease, it is important to capture all relevant costs
and outcomes associated with the intervention. In addition, migraine af f ects
predominately women and the natural course of disease suggests that prevalence of
migraine reduces signif icantly af ter menopause 59. Theref ore, the time horizon of themodel is set to 25 years in the base case. 25-years was deemed appropriate tocapture all material ef f ects on benef its and costs while considering the natural courseof the disease. Any longer time horizons would result to propagate the uncertainty ofshort-term clinical trial data though the model and inherently make any longer-term
estimates unreliable.
This approach considers that utility values dif f er between BSC and galcanezumab
treatment arms. This is based on an observed statistically signif icant treatment ef fect
between galcanezumab and BSC in the galcanezumab clinical trial program. In
addition, migraine headache days alone is poorly correlated with other specif ic
measures of health status used to capture the impact of migraine on HRQoL, thus
implying important aspects of HRQoL are not captured in the economic analysis,
which may underestimate galcanezumab’s cost ef f ectiveness compared to BSC. This
assumption was endorsed by NICE in the galcanezumab assessment45. For thecomparison to active treatments, the same utility values as f or galcanezumab are
applied.

72

4.2 分析で使用したパラメータ
ベースケース分析、シナリオ分析および感度分析の概要を（マルコフモ デルにおける推移確率等を含む） を以下に述べる。
表 4-3 分析で使用したパラメータ
Parameter

Episodic

Chronic

Perspective

Payer perspective

Payer perspective

Discount rate, costs andbenef its

2.0% and 2.0%

2.0% and 2.0%

Responder rate

50%

30%

Negative discontinuation rule at
3 months (responder
assessment)

Yes

Yes

Statistical distribution

Negative Binomial

Beta Binomial

Mean change f rom baseline in
MHD (BSC comparison)

Responder criterion

Responder criterion

Mean change f rom baseline in
MHD (active comparison)

Combined ef f icacy

Combined ef f icacy

No

No.

Yes

Yes

Switch to non-responder
mean change migraine
headache days and return tobaseline migraine headachedays

Switch to non-responder
mean change migraine
headache days andreturn to baselinemigraine headache days

Galcanezumab – 13 cycles

Galcanezumab – 13
cyclesPlacebo ef f ect of BSC
responders modelled beyond
month 12
Placebo ef f ect of BSCresponders modelled up to 12
monthsMean change Migraine
Headache Days applied to
discontinuers and nonresponders (BSC comparison)

Wane rate af ter discontinuation

BSC – immediately af ter the
next cycle

BSC – immediately af ter
the next cycle73Propranolol – immediately
af ter the next cycle
Valproic acid – immediately
af ter the next cycle

Discontinuation rate during theassessment period

Discontinuation rate in the
post-assessment period (af termonth 3)

Utility values

Acute medication use

Propranolol –
immediately af ter the
next cycle
Valproic acid –
immediately af ter the
next cycle

Galcanezumab -all-cause

Galcanezumab -all-cause

BSC – none

BSC – none

Propranolol – none

Propranolol – none

Valproic acid – none

Valproic acid – none

Galcanezumab - all-cause

Galcanezumab - allcause

BSC – none

BSC – none

Propranolol – persistency rate

Propranolol – persistency
rate

Valproic acid – persistency
rate

Treatment-specif ic utility
values (BSC comparison)

Valproic acid –persistency rate
Treatment-specif ic utility
values (BSC comparison)

Galcanezumab utility values(active comparison)

Galcanezumab utility
values (active
comparison)

Number of migraine headachedays with acute medication
use by categories estimatedf rom the galcanezumab trial
programNumber of migraine
headache days withacute medication use by
categories estimatedf rom the galcanezumab
trial program

A summary of the base case settings for the model and scenario analyses conducted (asdescribed below) is provided in 表 4-4. Extensive deterministic sensitivity analyses wereconducted to evaluate the robustness of the CE estimates considering the standard error forthe clinical efficacy parameters to assess the statistical uncertainty.
The scenario analyses involved replacing a parameter (or group of parameters) with anotherplausible value(s) in order to examine the impact of a new “scenario”. This provided a single
ICER estimate (for each comparator) associated with the new scenario. This type of analysis
can be used to assess both parameter and structural uncertainty.

74

表 4-4 Model setting
Parameter
General settings
Discount rates (costs, benef its)
Outcomes
Time horizon
Clinical outcomes
Response rate, CM
Response rate, EM
Mean Migraine Headache Days
improvement f or comparison in
BSC
Mean Migraine Headache Days
improvement f or comparison to
propranolol/valproic acid
Time of treatment waning af ter
discontinuation, Galcanezumab,
EM

Base case

Scenario

Costs: 2.0% andBenef its: 2.0% /year
Cost per QALY
25 years

0.0% and 4.0%/year30%
50%
Ef f icacy specif ic toresponders and nonresponders
Combined ef f icacy(pooled responder andnon-responder)
Based on washout dataf rom CGAH, 13 months(cycles) until baselinemigraine headache days

Cost per QALY
5, 10 and 45 years

Time of treatment waning af ter
discontinuation, Galcanezumab,
chronic

Based on washout dataf rom CGAH, 13 months(cycles) until baselinemigraine headache days

BSC waning ef f ect

BSC loses ef f ect af ter 12months of treatment
af ter assessment period% of patients on
propranolol and valproic
acid is inf ormed by ananalysis conducted inlocal Japanese claims
database (JMDC 2021
(Appendix 4-1))
Negative Binomial

50%
50%
Ef f icacy specif ic toresponders and nonresponders
Combined ef f icacy(pooled responder andnon-responder)
Assuming 5 cycles until
baseline migraine
headache days
Assuming 13 cycles f or
responder and 1 f or nonresponders
The post treatment per
data f rom the CGAI trial
was used. The analysis
f ocused on thegalcanezumab 120mg
dose. Based on theobserved data at 12
months and the change toMonth 16 an overallchange on MHD of 0.9
was converted to a permonth change of 0.23.
BSC loses ef f ect af ter 12months of treatment af ter
assessment period% of patients on
propranolol and valproic
acid is inf ormed by ananalysis conducted inlocal Japanese claims
database (JMDC 2021
(Appendix 4-1))
Beta-binomial

Beta-Binomial

Negative binomial

Propranolol and valproic acidwaning ef f ect

Distribution around Migraine
Headache Days, EM
Distribution around Migraine
Headache Days, chronic

75

Utilities
MSQ mapped to the EQ-5D using
CGAG, CGAH, CGAI, CGAN and
CGAW f or patients with 1 or 2 priorpreventive treatments or 3 ormore prior preventive treatments,
BSC
MSQ mapped to the EQ-5D using
CGAG, CGAH, CGAI, CGAN and
CGAW f or patients with 1 or 2 priorpreventive treatments or 3 ormore prior preventive treatments,
active treatment
Resource use
Discontinuation rate,
galcanezumab
Perspective

Treatment-specif ic utility
valuesTreatment-specif ic utility
valuesGalcanezumab utility
value

Galcanezumab utility
value

Kikui et al 202150
Due to all-cause

Kikui et al 202150
Due to adverse events(BSC only)
Payer

Payer

4.2.1 有効性･安全性等のパラメータの詳細
臨床パラメータは、ガルカネズマブの臨床試験において、過去に 1 剤または 2 剤の予防治療を中止（すなわち、2剤目または 3 剤目の予防治療）、1 剤の予防治療を中止（すなわち、2 剤目の予防治療）、2 剤の予防治療を中止（すなわち、3 剤目の予防治療）、または少なくとも 3 剤の予防治療の中止（すなわち、少なくとも 4 剤目の予防治療）の治療歴を持つ、反復性または慢性の片頭痛患者のサブグループから得た。以下に詳細を述べる。
The baseline patient characteristics used in the model are specific to the population of interest
and are shown in 表 4-5. No differences in population characteristics are assumed between
interventions. The age and gender parameters are used to calculate the background mortality(see Section 4.2.1). The mean baseline migraine headache days, shown below, is required tomodel the change from baseline in migraine headache days over the time horizon of the model.
See also section 4.2.1 for further description.
表 4-5 Baseline patient characteristics
Migraine populationN

Age (years)
Mean (SD)

Gender (%Female)Mean MHD(SD)

Episodic patients who fail 1 treatment
Episodic patients who fail 2 treatments
Episodic patientstreatments

who

fail

1

or

2

Episodic patients who fail >=3 treatments
Chronic patients who fail 1 treatment
Chronic patients who fail 2 treatments
Chronic patients who fail 1 or 2 treatments
Chronic patients who fail >=3 treatments
MHD – Migraine Headache Day
Source: /prd/ly2951742/hta_submission/output/shared/hta_japan/pooled_baseline_estimates.xlsx

Post-hoc analyses were conducted on the clinical trial program of galcanezumab for the
subgroup of episodic or chronic migraine patients with a76

history of 1 or 2 preventive treatment failures (ie. 2nd or 3rd line preventive treatment)
history of exactly 1 preventive treatment failure (ie. 2nd line preventive treatment)
history of exactly 2 preventive treatment failures (ie. 3rd line preventive treatment)
history of at least 3 prior preventive treatment failures (ie. ≥4th line preventive
treatment)
If more than one study of galcanezumab provided information for the same outcome andpopulation of interest, the corresponding treatment effect and variance considered in theequations of the Bucher method is a pooled estimator obtained through meta-analysis using
for binary outcomes the Mantel-Haenszel method. Pooling of continuous outcomes is conductedby assigning inverse variance weights to the individual studies. The inverse variance refers to
the relative effect of each individual study which is considered in the pooling. The long-term
open-label studies CGAJ and CGAP (patients with episodic and chronic migraine) informed thepost-assessment discontinuation rates.
The following data sources informed the baseline parameters as well as the efficacy and safetyparameters, where feasible:••••

表 4-6 Data sources of each parameters
Parameter
Baseline characteristics
Statistical distribution tomodel Migraine Headache
Days
Change from baseline in
Migraine Headache Days
Galcanezumab
Propranolol
Valproic Acid
BSC
Response rate
Galcanezumab and BSC

Episodic Migraine
CGAG, CGAH, CGAN, CGAW
Based on data from CGAG,CGAH and checked against
CGAJ, CGAN and CGAW

Chronic Migraine
CGAI, CGAW
Based on data from CGAI andchecked against CGAJ andCGAW

CGAG, CGAH, CGAN, CGAW
ITC
ITC
CGAG, CGAH, CGAN, CGAW

CGAI, CGAW
ITC^
ITC^
CGAI, CGAW

CGAG, CGAH, CGAN, CGAW

CGAI, CGAW

Propranolol
Valproic Acid
Discontinuation rate
Galcanezumab(assessment
period)Galcanezumab (postassessment
period)Treatment waning
Galcanezumab

ITC
JMDC 2021 (Appendix 4-1)

ITC^*
JMDC 2021 (Appendix 4-1)

4.2.1
4.2.1

CGAG, CGAH, CGAN, CGAW

CGAI, CGAW

4.2.1

CGAJ and CGAPCGAJ and CGAP

4.2.1

CGAH
CGAG, CGAH, CGAN, CGAI,
CGAW

CGAI
CGAG, CGAH, CGAN, CGAI,CGAWJMDC 2021 (Appendix 4-1)

JMDC 2021 (Appendix 4-1)

CGAG, CGAH, CGAN, CGAI,
CGAW

CGAG, CGAH, CGAN, CGAI,
CGAW

Utilities
Persistency analysis
Propranolol and Valproic
Acid
Number of Migraine
Headache Days with acutemedication class use

Section
4.2.1
4.2.1

4.2.1

4.2.1

4.2.1
4.2.3

4.2.1

^the indirect treatment comparison is based on data identified for the episodic migraine patient population. In the SLR, nodata was identified for chronic migraine.
*no information was identified for 30% or greater reduction in migraine headache days.

774.2.1.1 Distribution parameters
To approximate the distribution of monthly migraine headache days around the mean monthly
migraine headache day in the post assessment period (second part of the model), distributionsof monthly migraine headache days in patients with migraine were estimated based on theobserved mean migraine headache days using a parametric approach as described in Tannaand colleagues (2019) 60, such that a monthly migraine headache days distribution can be
estimated when no individual patient-level data is available. The patient level data from fourphase III randomized, placebo-controlled clinical trials and one phase III, long-term, openlabel safety study were used to estimate the distribution of monthly migraine headache daysin episodic and chronic migraine patients separately. The clinical development program
included one phase II study in Japanese outpatients with episodic migraine (CGAN), two phase
III studies in patients with episodic migraine (CGAG and CGAH) 61,62; one study in patientswith chronic migraine (CGAI) 63; and an open-label safety study (CGAJ) that evaluated patientswith episodic or chronic migraine for up to 1 year 64. CGAW was a 3-month double-blind,placebo-controlled study specifically conducted in patients with episodic or chronic migrainewith previous failure of 2 to 4 migraine preventive medication categories 65.
•
CGAI was used to estimate the distribution of monthly migraine headache days in chronic
migraine patients.
•
CGAG and CGAH were pooled and used to estimate the distribution in the episodic migraine
patient population.
•
CGAJ and CGAW were used to check the estimations performed with CGAI, CGAG and
CGAH.
•
CGAN was used to check the estimations performed with CGAG and CGAH in the Japanese
population.
The following steps were conducted on the patient-level data from double-blind and follow-up
periods of• the CGAI studies at every month from Month 1 to Month 12 in chronic migraine patients,
and independently,• the pooled CGAG and CGAH studies at every month from Month 1 to Month 10 in
episodic migraine patients.
1. At every month and for each treatment group, the observed migraine headache days
were plotted as bar charts with the fitted Poisson, negative binomial, binomial, betabinomial distribution and zero-inflated negative distributions. Each fitted distribution
was compared with the raw data using visual inspection of the plots and the residual
plot of observed versus simulated observations to assess overfitting. Goodness of fit ofthe distributions was assessed based on the root mean square error (RMSE). A smaller
RMSE indicates a better fit.
2. The estimation of a parametric approach to estimate the distributions of patients with
migraine headache days based only on the mean migraine headache days was donewith
• Negative binomial distribution that depends on the sample mean and a dispersion
parameter (bound between 0 and infinity), and• Beta-binomial distribution that depend on the sample mean with an intra-classcorrelation parameter (bound between 0 and 1)
3. For each of the fitted (negative binomial and beta-binomial) distributions from Step 1,
ordinary least square regression models were run to predict the second (dispersion or
intra-class correlation) parameter as a function of the mean number of migraine
headache days using a series of transformations.

78

4. The best fitting model was selected based on visual inspection, Akaike’s information
criterion (AIC) and parsimony at the different time points. Differences between theestimated and the fitted negative binomial distribution as well as residuals at eachmonth for each study treatment were also visually assessed.
5. The equations developed in Step 2 were assessed using independent datasets - patientswith episodic migraine from a safety study of galcanezumab (CGAJ), the phase 2 study
CGAN in Japanese outpatients suffering from episodic migraine, and the CGAW study
conducted in patients with previous failure to 2 to 4 migraine preventive medication
categories.
6. The equations were also tested using the following subpopulations of CGAG and CGAH,
CGAI, CGAN and CGAW• Patients with at least 8 migraine headache days at baseline from CGAG and CGAH,• Patients who failed at least 2 preventive treatments from CGAG and CGAH 66 and CGAI 67,• Patients with at least 8 migraine headache days and who failed at least 2 preventive
treatments from CGAG and CGAH
• Subpopulation of CGAW with patients who failed at least 3 migraine preventive
medication categories• Subpopulation of CGAN with patients who failed 1 or 2 migraine prevention treatments.
The negative binomial and beta binomial were chosen based on goodness of fit statistics andapplied to the episodic and chronic populations, respectively. The distributions were fitted to
the whole naïve and treatment experienced trial population migraine headache days from
CGAG, CGAH and CGAI, and checked against the naïve and treatment-resistant populations
from CGAI, CGAN and CGAW. 表 4-7 presents the results from the regression analysis,
associated with the negative binomial and beta-binomial distributions, to estimate thedispersion parameter around the mean migraine headache days.
表 4-7 Distribution parameters
Chronic migraine

Episodic migraine

Negative binomial distribution – dispersion parameter
4.7967 – 1.0206*mean + 0.0664*mean²

5.3837 – 2.0538*mean + 0.2526*mean²

Beta-binomial distribution – intra-class correlation parameter
Maximum of (0.4776 – 0.0158*mean) and 0.01

Maximum of (-0.0489+0.0741*mean-0.0076*mean²) and 0.01

図 4-2 displays the observed, estimated and fitted distributions, applying the equations
described in 表 4-3 using the intention to treat Japanese migraine population (CGAN). Basedon visual assessment, the fitted and estimated beta-binomial and negative binomial
distributions are similar, therefore the estimated negative binomial distribution is adequate toestimate the observed distribution of the monthly migraine headache days. The same applies
to the beta-binomial distribution.
Residuals of the estimated and fitted distributions were also plotted in 図 4-3 with the aim to79

visually assess them. Each graph displays the difference between the observed proportion ofpatients and the estimated (or fitted) proportion of patients for a given number of migraine
headache days ranging from 0 to 30 days.
Residuals between observed and estimated distributions for all are nearly within the 8% margin.
This indicates that the negative binomial and beta-binomial distributions are a good fit of theCGAN study data. Residuals from the fitted and estimated distributions are very similar,
indicating that the estimated distributions using the observed mean migraine headache days
are very similar to the fitted distributions.
図 4-2 Observed, f itted, and estimated parametric migraine headache days distributions at months
1, 2, and 3 - CGAN Episodic - All comers population - patients on Placebo andGalcanezumab

図 4-3 Residual errors of migraine headache days f or estimated and f itted negative binomial andbeta-binomial at months 1, 2, and 3 - CGAN Episodic - All comers population - patient
on Galcanezumab

804.2.1.2 Mean change from baseline in monthly migraine headache days
The change from baseline in migraine headache days is dependent upon population andassessed over the first 3 months after treatment initiation. The change from baseline is applied
to the population specific baseline migraine headache days (see 表 4-1). The number of
migraine headache days is limited in the model between the bounds of 0 and 30, based on thenumber of days in a treatment cycle from the galcanezumab trials. The mean change frombaseline in migraine headache days is applied to each health state in the model and used in
the distribution to calculate the number of patients experiencing each frequency of migraine
headache days. When comparing to propranolol or valproic acid, outcomes could only be
estimated from the ITC for mean change from baseline in monthly migraine headache days
which is not split by responder and non-responders but since the model stratifies the population
by responders and non-responders at the point of response assessment, the mean change of
migraine headache days considers both responders and non-responders in the analysis(‘combined criterion) when comparing galcanezumab to propranolol and valproic acid. Taking
this conservative approach may underestimate the cost effectiveness of galcanezumab
compared to propranolol or valproic acid.
Response based mean change from baseline in monthly migraine headache days(‘responder criterion’)For the analysis compared to BSC that considers direct head-to-head data from thegalcanezumab clinical trial program, the mean change from baseline in monthly migraine
headache days is linked to the response criteria (50% or greater response for episodic migraineor 30% or greater reduction for chronic migraine). Individual patient level data for each trial
were analysed and results for each trial subsequently pooled. The results for the mean change
from baseline in monthly migraine headache days stratified by responder and non-responder
are shown in 表 4-8. The change from baseline in monthly migraine headache days at month
3 has been analysed for patients who either met or didn’t meet the response definition at
month 3. The results of this analysis show that responders have typically a comparable meanchange from baseline in monthly migraine headache days when stratified by response status,

81

regardless of galcanezumab or BSC treatment. It is important to note that the proportion ofpatients achieving this change from baseline in monthly migraine headache days is greater inpatients receiving galcanezumab compared to BSC in the galcanezumab clinical trial program.
This suggests that the difference in treatment is mainly driven by differences in response rates.
表 4-8 Change f rom baseline in Migraine Headache Days f or responders and non-responders
at month 3 – BSC comparison only (‘responder criterion’)
Population andintervention

Responders
Mean CFB in
N
MHD (SE)30% response rate – Chronic Migraine

Non-responders
Mean CFB in
N
MHD (SE)

SourcePatients who have experienced 1 or 2 prior medication failures (ie. 2nd or 3rd line of preventive treatment)
Galcanezumab
BSC

Table B.2.c.3 [2] and Table B.2.c.4[2]Patients who have experienced ≥3 prior medication failures
Galcanezumab
BSC

Table B.2.d.3 [2] and Table B.2.d.4[2]Patients who have experienced 1 prior medication failure (ie. 2nd line of preventive treatment)
Galcanezumab
BSC

Table B.2.a.3 [2] and Table B.2.a.4[2]Patients who have experienced 2 prior medication failures (ie. 3rd line of preventive treatment)
Galcanezumab
BSC

Table B.2.b.3 [2] and Table B.2.b.4[2]50% response rate – Episodic Migraine
Patients who have experienced 1 or 2 prior medication failures (ie. 2nd or 3rd line of preventive treatment)
Galcanezumab
BSC

Table B.1.c.1 [1] and Table B.1.c.2[1]Patients who have experienced ≥3 prior medication failures (ie. ≥4th line preventive treatment)
Galcanezumab
BSC

Table B.1.d.1 [1] and Table B.1.d.2[1]Patients who have experienced 1 prior medication failure (ie. 2nd line of preventive treatment)
Galcanezumab
BSC

Table B.1.a.1 [1] and Table B.1.a.2[1]Patients who have experienced 2 prior medication failures (ie. 3rd line of preventive treatment)
Galcanezumab
BSC

Table B.1.b.1 [1] and Table B.1.b.2[1]50% response rate – Chronic migraine
Patients who have experienced 1 or 2 prior medication failures (ie. 2nd or 3rd line of preventive treatment)
Galcanezumab

Table B.2.c.1 [2] and Table B.2.c.2

82

BSC

[2]

Patients who have experienced ≥3 prior medication failures (ie. ≥4th line preventive treatment)
Galcanezumab
BSC

Table B.2.d.1 [2] and Table B.2.d.2[2]Patients who have experienced 1 prior medication failure (ie. 2nd line of preventive treatment)
Galcanezumab
BSC

Table B.2.a.1 [2] and Table B.2.a.2[2]

Patients who have experienced 2 prior medication failures (ie. 3rd line of preventive treatment)
Galcanezumab
BSC

Table B.2.b.1 [2] and Table B.2.b.2[2]

BSC – Best Supportive Care, CFB – Change from Baseline, MHD – Migraine Headache Days
Source:[1]¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Base.case.em___t
fls.rtf and[2]¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Base.case.cm___tf
ls.rtfCombined mean change from baseline in monthly migraine headache days(‘combined criterion’)
The mean change from baseline in monthly migraine headache day was populated from the
ITC compared to propranolol or valproic acid. The ITC estimated the change from baseline
directly for galcanezumab compared to propranolol or valproic acid. Since the model splits the
population by responders and non-responders at the point of assessment of response (month3), the mean change is thus applied to both groups when looking at a combined population of
responders and non-responders for the comparison to propranolol or valproic acid. The
response assessment still takes place to account for the negative discontinuation rule, definedby either 50% (EM) or 30% (CM) or greater reduction in monthly migraine headache days at
3 months. It is important to highlight that the ITC to propranolol was based on change frombaseline in migraine headache days (combined criterion) at month 3 as well as response rate
at month 3 taken directly from the galcanezumab clinical trial program, and one randomized,
26-week core double-blind period, multicentre trial enrolling episodic migraine patients in 13
countries. The study reporting data on propranolol included an 8 weeks of dose up-titration
followed by 18 weeks of stable propranolol dose 34. The outcomes for propranolol were reported
for the entire 26-week core double-blind treatment period, which is longer than the timepoint
at which galcanezumab data were assessed (ie. 3 months to align with the cost-effectivenessanalysis). In addition, the effectiveness of propranolol reported in Diener et al 200434 wasbased on a propranolol dose of 160mg once daily. The median average daily dose for the core
double-blind phase (titration and maintenance) was 129.6mg/day. This median dose isapproximately 6 times higher than the mean dose of propranolol (21.59mg/day) reported in
the JMDC analysis conducted in local Japanese data (JMDC 2021 (Appendix 4-1)). Similar topropranolol, the average dose reported in the clinical trials for valproic acid is higher than what
is observed in Japanese routine clinical practice. The average dose of valproic acid reported in
the studies considered for the ITC ranged from 871mg/day to 1087mg/day, which is up to 3
times higher than the Japanese mean average dose of valproic acid of 334.76mg/day (JMDC
2021 (Appendix 4-1)). Thus the effectiveness of propranolol and valproic acid applied in themodel represents the upper end of the effectiveness that would be expected in the Japanesereal-life setting.
表 4-9 shows the mean change f rom baseline in monthly migraine headache days f or thedif f erent populations considered in the model.

83表 4-9 Change f rom baseline in Migraine Headache Days f or total population at month 3(‘Combined criterion’)N

CFB in MHD(SE)

SourceEpisodic migraine
Patients who have experienced 1 or 2 prior medication failures
Galcanezumab
BSC

Table B.1.c [1]Indirect comparison of galcanezumab versus propranolol:
mean difference of* (random effects model), Table
B.1.c [1]Indirect comparison of galcanezumab versus valproic
Valproic Acidacid: mean difference of(random effects model),Table SA2.1.c [1]Patients who have experienced 1 prior medication failure
Propranolol

Galcanezumab
BSC

Table B.1.a [1]Indirect comparison of galcanezumab versus propranolol:
mean difference of* (random effects model), Table
B.1.a [1]Indirect comparison of galcanezumab versus valproic
Valproic Acidacid: mean difference of(random effects model),Table SA2.1.a [1]Patients who have experienced 2 prior medication failures
Propranolol

Galcanezumab
BSC
Propranolol
Valproic Acid

Table B.1.b [1]Indirect comparison of galcanezumab versus propranolol:
mean difference of(random effects model), Table
B.1.b [1]Indirect comparison of galcanezumab versus valproic
acid: mean difference of(random effects model),Table SA2.1.b [1]Chronic migraine
Patients who have experienced 1 or 2 prior medication failures
Galcanezumab
BSC

Table B.2.c [2]Indirect comparison of galcanezumab versus propranolol:
mean difference of* (random effects model), Table
B.2.c [2]Indirect comparison of galcanezumab versus valproic
Valproic Acidacid: mean difference of(random effects model),Table SA2.1.f [2]Patients who have experienced 1 prior medication failure
Propranolol

Galcanezumab
BSC
Propranolol

Table B.2.a [2]Indirect comparison of galcanezumab versus propranolol:
mean difference of(random effects model), Table
B.2.a [2]84Indirect comparison of galcanezumab versus valproic
acid: mean difference of(random effects model),Table SA2.1.d [2]Patients who have experienced 2 prior medication failures
Valproic Acid

Galcanezumab

Table B.2.b [2]

BSC

Indirect comparison of galcanezumab versus propranolol:
mean difference of* (random effects model), Table
B.2.b [2]Indirect comparison of galcanezumab versus valproic
acid: mean difference of(random effects model),Table SA2.1.e [2]Propranolol
Valproic Acid*p<0.05. BSC – Best Supportive Care, CFB – Change from Baseline, MHD – Migraine Headache Days.
Source:[1]¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_ICpropanolol_validated_v4.xlsb.xlsx___Base.case.em___t
fls.rtfand[2]¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_ICpropanolol_validated_v4.xlsb.xlsx___Base.case.cm___t
fls.rtf

4.2.1.3 Response rates
Assessment of response has been included in the model in line with clinical guidelines,
specifically the optimal use guideline10 and the galcanezumab package insert1 . Response totreatment is assessed at month 3. To identify the proportion of patients continuing treatment
beyond month 3, the base case assumes a response rate as a reduction in monthly migraine
headache days of 50% or greater from baseline for patients with EM and 30% or greater forchronic migraine patients. This response criterion is considered clinical meaningful in its
respective patient population42 ,43 .
The proportion of patients with a history of 1 or 2 prior preventive treatment failures, exactly
1 failure, exactly 2 failures or at least 3 prior preventive treatment failures experiencing a 30%
or 50% or greater reduction in migraine headache day response rate was informed by CGAG,
CGAH, CGAN and CGAW for episodic migraine and CGAI and CGAW for chronic migraine. 表 410 shows the proportion of patients with a 50% or greater reduction in monthly migraine
headache days and 表 4-11 the results for 30% or greater reduction in monthly migraine
headache days. Patients classified as non-responders are transitioned to the off-treatment
health state where the migraine headache days returns to the baseline level.
Patients in the BSC arm who respond to treatment were assumed to remain on-treatment andmaintain their responder mean migraine headache days change and placebo effect dissipates
after 12 cycles resulting in monthly migraine headache days returning back to baseline level.
Responders who do not discontinue for any reason in the galcanezumab arm are assumed tomaintain their mean change monthly migraine headache days until the end of the modelled
time horizon. Patients who discontinue galcanezumab treatment for any reason wane back tobaseline migraine headache days over 13 cycles. Patients on propranolol or valproic acid who
respond to treatment will discontinue treatment over a total 24 months based on Japanesereal-world evidence (JMDC 2021 (Appendix 4-1)).
表 4-10 Probability of achieving a 50% or greater reduction in migraine headache days atmonth 3n/N

Episodic migraine

Response
rate

Source85

Patients who have experienced 1 or 2 prior medication failures (ie. 2nd or 3rd line preventive
treatment)
Galcanezumab
Table A.1.c [1]
BSC
Indirect comparison of galcanezumab versus
Propranolol
propranolol: relative risk:(random effects
model), Table A.1.c [1]Valproic Acid
JMDC 2021 (Appendix 4-1)
Patients who have experienced at least 3 prior medication failures i(e. ie. ≥4th line preventive
treatment)
Galcanezumab
Table A.1.d [1]
BSC
Patients who have experienced 1 prior medication failure (ie. 2nd line preventive treatment)
Galcanezumab
Table A.1.a [1]BSC
Indirect comparison of galcanezumab versus
Propranolol
propranolol: relative risk:(random effects
model), Table A.1.a [1]Valproic Acid
JMDC 2021 (Appendix 4-1)
Patients who have experienced 2 prior medication failures (ie. 3rd line preventive treatment)
Galcanezumab
Table A.1.b [1]
BSC
Indirect comparison of galcanezumab versus
Propranolol
propranolol: relative risk:(random effects
model), Table A.1.b [1]Valproic Acid
JMDC 2021 (Appendix 4-1)
Chronic migraine
Patients who have experienced 1 or 2 prior medication failures (ie. 2nd or 3rd line preventive
treatment)
Galcanezumab
Table A.2.c [2]BSC
Indirect comparison of galcanezumab versus
Propranolol
propranolol: relative risk:(random effects
model), Table A.2.c [2]Valproic Acid
JMDC 2021 (Appendix 4-1)
Patients who have experienced at least 3 prior medication failures (ie. ≥4th line preventive
treatment)
Galcanezumab
Table A.2.d [2]BSC
Patients who have experienced 1 prior medication failure (ie. 2nd line preventive treatment)
Galcanezumab
Table A.2.a [2]BSC
Indirect comparison of galcanezumab versus
Propranolol(random effects
propranolol: relative risk:
model), Table A.2.a [2]Valproic Acid
JMDC 2021 (Appendix 4-1)
Patients who have experienced 2 prior medication failures (ie. 3rd line preventive treatment)
Galcanezumab
Table A.2.b [2]
BSC
Indirect comparison of galcanezumab versus
Propranolol
propranolol: relative risk:(random effects
model), Table A.2.b [2]Valproic Acid
JMDC 2021 (Appendix 4-1)

BSC – Best Supportive Care, N/A – not applicable
Source:[1]¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Base.case.em___t

86

fls.rtf
and[2]¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_V4.xlsb.xlsx___Base.case.cm___t
fls.rtf

表 4-11 Probability of achieving a 30% or greater reduction in migraine headache days atmonth 3
n/N

Response
rate

SourceChronic migraine
Patients who have experienced 1 or 2 prior medication failures (ie. 2nd or 3rd line preventive
treatment)
Galcanezumab
Table A.2.c.1 [2]
BSC
Assumption same relative risk assumed as for 50%
RR given lack of data, Indirect comparison of
Propranolol
galcanezumab versus propranolol: relative risk:(random effects model), Table A.2.c [2]Valproic Acid
JMDC 2021 (Appendix 4-1)
Patients who have experienced at least 3 prior medication failures (ie. ≥4th line preventive
treatment)
Galcanezumab
Table A.2.d.1 [2]
BSC
Patients who have experienced 1 prior medication failure (ie. 2nd line preventive treatment)
Galcanezumab
Table A.2.a.1 [2]
BSC
Assumption same relative risk assumed as for 50%
RR given lack of data, Indirect comparison of
Propranolol
galcanezumab versus propranolol: relative risk:(random effects model), Table A.2.a [2]Valproic Acid
JMDC 2021 (Appendix 4-1)
Patients who have experienced 2 prior medication failures (ie. 3rd line preventive treatment)
Galcanezumab
Table A.2.b.1 [2]
BSC
Assumption same relative risk assumed as for 50%
RR given lack of data, Indirect comparison of
Propranolol
galcanezumab versus propranolol: relative risk:(random effects model), Table A.2.b [2]Valproic Acid
JMDC 2021 (Appendix 4-1)

BSC – Best Supportive Care, N/A – not applicable
Source:[1]¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Base.case.em___t
fls.rtfand[2]¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_Icpropanolol_validated_v4.xlsb.xlsx___Base.case.cm___tf
ls.rtf

4.2.1.4 Persistency to oral preventive migraine treatment
Low adherence and persistence with current migraine preventive medications
The success of migraine prophylaxis is crucially dependent on patient adherence to treatment68.
In a systematic review of 33 relevant studies (observational, n=14; RCT, n=19), it wasreported that adherence and persistence to propranolol exhibited a downward trend overtime,with rates of adherence and persistence below acceptable thresholds (≤80%) within 6 months
of initiating therapy68 .
Adherence to antiepileptics, antidepressants, and β-blockers for migraine prophylaxis wasreported in 4634 patients identified from a large US health insurance claims database 69. Poor
rates of adherence (with nonadherence indicated by a medication possession ratio [MPR] of<0.80) were observed regardless of drug type, with mean MPR values of 0.48, 0.51, and 0.51

87

for antidepressants, antiepileptics, and β-blockers, respectively, at 6 months69 . Rates of
nonadherence at 6 months for each drug class were 73.4%, 70.2%, and 67.6%, respectively.
Given guideline recommendations that preventive medications should be used for 2–3 months
to ascertain effectiveness it is concerning that relatively few patients may remain adherent
over this timescale69 .
Two studies using a large US healthcare claims database have specifically evaluated adherence
and persistence to preventive medications in patients with CM 70,71. In the first study, adherence
to commonly prescribed oral treatments for migraine prophylaxis (antidepressants,
antihypertensives, and antiepileptics) was calculated using both the MPR and proportion ofdays covered (PDC; the formulas for which are described in 図 4-4) in 8,688 patients. When
MPR ≥80% was used to classify rates, only 29% and 20% of patients were adherent at theend of 6 and 12 months of therapy, respectively (図 4-3). Using PDC ≥80% as the threshold,even fewer patients were adherent at 6 or 12 months of follow-up (図 4-4).
図 4-4 Rate of adherence to oral migraine preventive medications in patients with CM70

MPR is calculated as the total number of days’ supply divided by the total number of days in the follow-up period.
PDC is calculated as the total number of days the drug is available divided by the total number of days in the follow-up
period.
CM, chronic migraine; MPR, medication possession ratio; PDC, proportion of days covered.

In the second study, persistence, defined as the length of time a patient remains on a drug
after initial prescription with migraine preventive agents, was evaluated in 8707 patients with
CM71 . Persistence rates to the initial medication were low at both 6-month and 12-monthfollow-up (25% and 14%, respectively)71. Furthermore, the data indicated that switching iscommon, and persistence decreases even further as a patient cycles through multiple
preventive agents. The average time to discontinuation was 2–3 months. This correspondswith guideline recommendations for an adequate preventive drug trial; however, Kaplan–Meiercurves demonstrated a sharp drop-off in persistence at 30 days, with over half of patients
discontinuing by ~60 days (図 4-5). Similar trends regarding time to discontinuation wereobserved with the second and third preventive drug.

88図 4-5 Time to discontinuation up to 12 months’ f ollow-up f rom the initial prophylactic, stratified
by class of oral migraine preventive medication71

An additional US study assessed the persistency of migraine patients with propranolol/timolol(N=2718) or divalproex sodium (N=1644) using the Health Core Integrated Research Database.
Similar to the previous studies persistency was low with more than half of the patients notcontinuing their treatment beyond 60 days post-index and less than 10% of patients were stillon treatment 306 days post-index (図 4-6 72).
図 4-6 Persistency with propranolol/timolol or divalproex sodium in patients with migraine72

4.2.1.4 Persistency on Propranolol and Valproic Acid (JMDC 2021 (Appendix 4-1))

89Given the lack of published Japanese data on persistency rates for propranolol and valproic
acid, an analysis of the JMDC dataset was performed to analyse the proportion of Japanesepatients on propranolol and valproic acid treatment across 24-months. To meet this objective,
adult patients enrolled in the JMDC dataset with a diagnosis for migraine (G43) and aprescription for both preventive and acute treatment for migraine with an index date between
July 2013 – December 2018 were analysed. Over a 24 months follow-up period, patients wereassessed on whether they continued valproic acid or propranolol by line of treatment.
Discontinuation was defined as ending treatment with the preventive portion of the index
migraine treatment regimen without evidence of another refill for the same medication within
60 days of exhausting the drug supply for the prior prescription. The grace period of 60 days
was adapted to 35 days in case the medication is categorized ‘as needed’ or the prescriptions
days are unknown. Patients who refilled the medication of interest after 61 days are consideredas discontinuers. This also applies to patients who switch back to their initial preventive
medication. The results of this analysis are displayed in 図 4-7.
図 4-7 Persistency rate with propranolol or valproic acid treatment in Japanese routine clinicalpractice (JMDC 2021 (Appendix 4-1))

The result of the JMDC analysis shows a comparable trend to the non-Japan specific studies
discussed in the previous section with a sharp drop off by month 3 and a low number of patientsremaining on treatment at 6 months, respectively at 12 months irrespective of line oftreatment. All patients discontinued treatment at 24 months. In contrast to the analysis
conducted by Hepp and colleagues 201771 or Yaldo and colleagues 200872 , a greater proportionof patients were still on treatment at month 3 and 6.
The pattern displayed in 図 4-7 is modelled in the cost-effectiveness analysis by consideringthat patients stop treatment at month 6, month 9 and month 12. This is a conservative
assumption as this would imply that all patients still on treatment at month 12 remain on
treatment and accrue the benefits of the associated reduction in migraine headache days andrelated HrQoL gain up to month 24 despite the fact that patients drop out every month (see
図 4-7). No additional discontinuation due to adverse event or for other reasons is consideredin the model beyond the proportion of patients being persistent at month 6, month 9 or month
12 to avoid double-counting (see 表 4-12).

90

表 4-12 Proportion of patients persistent with propranolol or valproic acid at month 6, 9 and 12(JMDC 2021 (Appendix 4-1))
Fail 1 or 2 treatments(ie. 2nd or 3rd line)
Persistency rate on propranolol treatment
6 months
35.92%
9 months
25.24%
12 months
16.02%
Persistency rate on valproic acid
6 months
38.25%
9 months
25.65%
12 months
18.96%

Fail 1 treatment(ie. 2nd line)

Fail 2 treatments(ie. 3rd line)

37.06%
26.57%
16.78%

33.33%
22.22%
14.29%

38.67%
26.33%
19.34%

28.95%
10.53%
10.53%*since the JMDC analysis was done for the overall migraine population not by subtype, the same values are applied for episodic and chronic
migraine patients

4.2.1.5 Discontinuation
As displayed in 図 4-1, patients can discontinue from treatment in the following ways:
1. Discontinuation due to lack of response (50% or greater response rate for EM and
30% or greater response rate for CM patients) at the end of the assessment period(month 3) – See description below: “Discontinuation due to lack of response (50%or greater response rate for EM and 30% or greater response rate for CM patients)
at the end of the assessment period”
2. Discontinuation due to all-cause during the first 3 months – See description below“Discontinuation due to any reason during the assessment period”
3. Long-term discontinuation due to all-cause in the post assessment period (month 4
onwards) – See description below “Long-term discontinuation due to any reason(after month 3)
4. Discontinuation due to lack of persistency in the post assessment period (month 4
onwards) – See description below “Long-term discontinuation due to any reason(after month 3)
表 4-13 中止理由の詳細
中止理由の詳細
中止理由
Galcanezumab
1.有効性の判定

Propranolol (Valproic BSC
acid)
投与開始後 3 か月時点にて有効性を判定し、以下の基準を満たさない場合は中止
EM: MHD のベースラインからの 50%減少
CM: MHD のベースラインからの 30%減少
投与開始後 3 か月時点に 本理由での中止は適用し 本理由での中止は適用して、表 4-14 に示す割合で ない
ない
中止する。

2.投与開始 後 3か月時点での All
cause
discontinuation
3.投与開始 後 4 投与開始後 4 か月以 降
か 月 以 降 の All に、表 4-15 に示す月率にcauseて中止する。
discontinuation
4.JMDCの 本理由での中止は適用しPersistency に基 ない

本理由での中止は適用し 本理由での中止は適用しない
ない

投与開始後 6、9、12 か月時点にて、表 4-12 に示す
割合で中止する。

本理由での中止は適用し
ない

91

づ
く
Discontinuation
Discontinuation due to lack of response (50% or greater response rate for EM and
30% or greater response rate for CM patients) at the end of the assessment period
All patients considered to be non-responders at month 3 transition to an off-treatment healthstate where they receive BSC, ie. acute medication. The proportion of patients who discontinue
due to lack of efficacy (defined as not meeting the response threshold of 50% for episodic
migraine or 30% for chronic migraine at month 3) is informed directly from the clinical trial
program for galcanezumab and BSC. Data from the indirect treatment comparison for
propranolol informed the proportion of patients who are responders to propranolol at 3 months.
Due to lack of available data for valproic acid, an indirect treatment comparison could not be
performed, hence data from the Japan routine clinical practice (JMDC 2021 (Appendix 4-1))
were used as a proxy instead (see 表 4-10).
Discontinuation due to any reason during the assessment period
Patients on galcanezumab could discontinue due to all-cause at the end of the assessment
period. The values used in the model are based on the ITT population of CGAG, CGAH, CGAI,
CGAN and CGAW independently for episodic and chronic migraine. Discontinuation rates for
CGAG, CGAH and CGAN were adjusted to 3-month rates assuming events leading todiscontinuation are equally distributed across the 6-months double-blind treatment period.
After discontinuing galcanezumab treatment, patients go back to baseline monthly migraine
headache days over time, which was informed by the washout period data from galcanezumab
trials. 表 4-14 summarises the discontinuation rate for the assessment period. Discontinuation
due to adverse events is explored in a scenario analysis. No discontinuation rate due to allcause is assumed for BSC, which is a conservative assumption since patients discontinued theplacebo-arm in the clinical trials of galcanezumab. No discontinuation rates are considered forpropranolol and valproic acid since discontinuation is captured by the persistency analysis of
the JMDC dataset.
表 4-14 Probability of discontinuation due to all cause discontinuation or adverse events at theend of the assessment period
Probability of
discontinuation

SourceAll-cause discontinuation
Episodic migraine – patients, for whom prior preventive treatments failed
Table S.1.a, CGAN, CGAG and CGAH adjusted
Galcanezumab
for 3 months assuming linear distribution of
discontinuation [3]Chronic migraine - patients, for whom prior preventive treatments failed
Galcanezumab
Table S.2.a[3]Discontinuation due to AE
Episodic migraine – patients, for whom prior preventive treatments failed
Table S.1.b, CGAN, CGAG and CGAH adjusted
for 3 months assuming linear distribution ofGalcanezumab
discontinuation, CGAW had zero events and is
manually added in the calculation [3]Chronic migraine - patients, for whom prior preventive treatments failed
Galcanezumab
Table S.2.b [3]Source:92

[3]Y:¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_ICpropanolol_validated_v2.xlsb.xlsx___Base.case.safet
y___tfls.rtf

Long-term discontinuation due to any reason (after month 3)
After the initial 3 months of treatment, patients who did respond to treatment could further
discontinue galcanezumab due to all-cause (e.g. loss of efficacy, patients decision, adverse
events). Data from both CGAP and CGAJ, two phase III, multicentre, randomised, open-label
studies assessing the long-term (12-month) safety and tolerability of galcanezumab in patientswith episodic migraine or chronic migraine were pooled to inform the discontinuation rate for
galcanezumab53,54. 表 4-15 summarises the discontinuation rate after the assessment period(month 3). Based on the data from the studies, galcanezumab was well-tolerated and hasquite low discontinuation rate due to AE after month 3. Considering the safety profile and themaintenance of the efficacy of galcanezumab, it was reasonable to anticipate low
discontinuation rate after the assessment period if the patient was evaluated as a responderat the time of month 3. Discontinuation due to adverse events is explored in a scenario analysis.
No discontinuation rate is assumed for BSC up to 12 months after which the placebo effectdissipates. To avoid double counting, no additional discontinuation rate beyond the proportionof patients being persistent at month 6, 9 and 12 is considered for propranolol or valproic acidduring the post-assessment period. All patients on valproic acid and propranolol discontinue
treatment by 24 months in line with the JMDC analysis (Appendix 4-1).
表 4-15 Rate of discontinuation beyond assessment period (after months 3)
All-cause discontinuation
Galcanezumab
Discontinuation due to AE
Galcanezumab

Probability of
discontinuation

SourceTable S.1.c, adjusted for monthly cycle rate,
same rate is applied for episodic and chronic
migraine [3]Table S.1.d, adjusted for monthly cycle rate,
same rate is applied for episodic and chronic
migraine [3]Source:[3]Y:¥prd¥ly2951742¥hta_submission¥output¥shared¥hta_japan¥masterfile_meta_ICpropanolol_validated_v2.xlsb.xlsx___Base.case.safet
y___tfls.rtf

Mean change of migraine headache days after discontinuation (BSC, propranolol orvalproic acid)
For patients on BSC, propranolol or valproic acid who discontinue for non-response, the meanchange monthly migraine headache days return to the baseline value based on patients losing
their effect immediately in the next month.
For patients on BSC who respond at the point of assessment at month 3, it is assumed thatthese patients return to baseline monthly migraine headache days after a total of 12 cycles,
ie. the placebo effect dissipates. A return to baseline monthly migraine headache days for both
BSC responders and non-responders means that the placebo effects encountered in the trial
are negligible in the model. This assumption is based on the NICE committee’s preferredassumptions from NICE technology appraisal of fremanezumab44 where it states that theplacebo response observed during the clinical trial would not be seen in clinical practice. This
assumption was also accepted by NICE in their guidance of galcanezumab45 . The base caseassumptions for the BSC arm is applied to both the episodic and chronic migraine analyses.

93For patients on propranolol or valproic acid who respond at the point of assessment at month3, it is assumed that these patients return to baseline monthly migraine headache days after
24 months in line with the persistency analysis conducted in the JMDC database, which showsthat patients stop being on their 2nd or 3rd line treatment by month 24 (see 図 4-7). No
additional discontinuation rate was considered for propranolol or valproic acid to avoid double
counting.
Given the lack of washout period data and that propranolol and valproic acid are daily orals it
is assumed that the half-life cycle of the treatment is very short. Therefore, similar to BSC,
patients on valproic acid and propranolol return to baseline migraine headache days
immediately after they discontinued treatment.
Mean change of migraine headache days after discontinuation (galcanezumab arm)
Patients who discontinue galcanezumab, due to either non-response or all-cause reasons,transition to the off-treatment health state, in which they wane back to baseline monthly
migraine headache days, are assumed to receive BSC only. These patients are assigned thenon-responder mean change monthly migraine headache days and return to baseline monthly
migraine headache days values over time. The wane back to baseline monthly migraine
headache days occurs at different rates for patients with episodic and chronic migraine. In thebase case, EM patients who discontinue treatment return to baseline over 13 cycles based on
the last observation of the double-blind treatment period (month 6) and the monthly migraine
headache day reductions observed in the washout period from CGAH (ie. month 7-month 10).
A simple quadratic function was fitted to the last five observations (month 6-10) (shown in 図4-8) to predict the time required when migraine headache days return to baseline, whichx(R2=0.9926).
resulted in the following function: y=x2+
図 4-8 Washout data –CGAH73

94

For the patients with chronic migraine, the same treatment waning is assumed as for episodic
migraine, ie. 13 cycles.
A scenario analysis is being conducted, which is informed by the open-label extension of the
CGAI trial (shown in 図 4-9). During the OLE period all patients received galcanezumab frommonth 3 to month 12 and in contrast to EM, data on discontinued patients cannot be compared
between galcanezumab treatment and placebo. Due to this, the rate of mean change inmonthly migraine headache day decline has been calculated from the wash out period frommonth 12 to 16. A rate of decline of 0.225 per cycle was applied to the chronic population
based on this data. The calculated rate of change is used for all chronic populations in a
scenario analysis, however due to differences in treatment efficacy and baseline values for
migraine headache days, the time it takes for the return to baseline is different for each
population.
図 4-9 Washout data – CGAI

To note, the estimated rate of treatment waning after discontinuation for the galcanezumabarms is based on the total population enrolled in the pivotal trials.
Summary mean change
A summary of the mean change and the data sources over time has been provided in 表 4-16.

95

表 4-16 Summary of mean change in monthly Migraine Headache Days
Discontinuation due
Model treatment
to all-cause –Responders
Non-respondersarm
assessment period· One-of f rate of% (EM) or%· Active treatment(CM) applied once at· Continue with
until month 3 thentime of response
switch to BSC
active treatment
assessment (month 3)
Non-responder· Maintain responder ·· Discontinue active
stratif iedmean
Migraine Headache
treatment and switch
Migraine
Days until end of time change
to BSCHeadache Days f rom
horizon (comparison· Switch to nonbaseline applied f rom
to BSC)
responder Migraine
Galcanezumab
month 3 and ef fect
· Maintain combined
Headache Days and
wanes
back
to
(responder and nonwane back to baseline
baseline
Migraine
responder) Migraine
Migraine Headache
Headache Days over
Headache Days until
Days over time (overtime (over 13 cycles)
end of time horizon
13 cycles f or EM and· Baseline Migraine(comparison to
CM)
HeadacheDays
propranolol or· Baseline Migraine
maintained until end
valproic acid)
Headache Daysof time horizon
maintained until endof time horizon· BSC until day 90
response assessment· BSC responder· BSC treatment until
mean changemonths 3
Migraine Headache· Mean change f rom
baseline until month 3· 0% discontinue due Days waned back toBest Supportive
Migraine
Headacheto all-cause withinbaseline Migraine
Care (BSC)
Days then switch totrial period.
Headache Days overbaseline
Migraine
12 cycles
Headache Days in the· Baseline Migraine
next cycle
Headache Days
maintained until endof time horizon

Discontinuation due
to all-cause – post
assessment· Per cycle
discontinuation rate of% applied until
end of time horizon· Switch to nonresponder stratif iedmean change Migraine
Headache Days f rom
baseline applied f rom
month 3 and ef f ect
wanes back tobaseline Migraine
Headache Days overtime (over 13 cycles)· Baseline Migraine
Headache Days
maintained until endof time horizon· 0% discontinue due
to all-cause per cycle· No patients remain
on BSC mean change
Migraine HeadacheDays in the post
assessment period
beyond 12 months

96

Propranolol/valproicacid· No discontinuation
assumed in the f irst 3
months· Continue withactive treatment· Persistency
analysis inf orms
proportion of patients
who discontinue
treatment at month
6, month 9 andmonth 12
· Patients persisting
to treatment maintaincombined population(responder and nonresponder) MHDs
until end of 24months of treatment· Baseline Migraine
Headache Days
maintained until endof time horizon· Active treatment
until day 90 thenswitch to BSC· Switch to combined
population(responder and nonresponder) Migraine
Headache Days andwane back to baselinemeanchangeMigraine
HeadacheDays in the next
cycle.
· Baseline Migraine
HeadacheDays
maintained until endof time horizon· Patients are
stopping treatment inline with thepersistency analysis
conducted in JMDC atmonth 6, month 9 andmonth 12
· Switch to combined
population (responder
and non-responder)
Migraine HeadacheDays and wane backto baseline meanchange Migraine
Headache Days in thenext cycle.
· Baseline Migraine
Headache Days
maintained until endof time horizon

97

4.2.1.6 Adverse events
Adverse events have not been explicitly modelled due to the small number of patients
experiencing serious adverse events, their transient nature, the limited impact these would
have on resource use and subsequently on the overall results, and to avoid double counting
since discontinuation due to all-cause has been included in the model.
The impact of the adverse events on the utility values from the trial is still included in themodel by modelling discontinuation due to all-cause, therefore explicitly capturing the impactof adverse events on health-related quality of life would lead to double counting.
4.2.1.7 Mortality
In the cost-effectiveness analysis, only all-cause mortality, based on the national Japanese life
tables51 , is considered. Applying the population specific characteristics (see 表 4-3) to the life
tables, allows the calculation of a monthly (cycle) mortality rate. Given conflicting evidence
shown in the literature regarding migraine-specific mortality, no additional mortality rate wasconsidered in the model 74,75.
4.2.2 QOL 値の詳細
Quality of life in migraine
Migraine is a complex neurological condition and its impact on patient’s HRQoL is multifaceted.
Health-state utility values (HSUVs) were estimated using the migraine-specific quality of life
questionnaire (MSQ) collected within the trials, with estimates predicted on data for reductions
in migraine headache days. The interplay between the complex nature of the ‘ictal’ burden(that is, the experience of the migraine attack itself) and ‘interictal burden (that is, theexperience in between migraine attacks) on HRQoL is unlikely captured through reduction in
migraine headache days alone. Thereby underestimating the impact preventative treatments
such as galcanezumab have on HRQoL and also its cost effectiveness particularly compared tobest supportive care treatments. Hence, the application of a treatment effect to HSUVs may
capture the additional HRQoL benefit of preventative treatment such as reductions in theintensity/severity of pain associated with migraine attacks, disability caused by migraine
attacks and the interictal burden between attacks.
Several studies have been performed to qualitatively and quantitatively capture the complex
nature of symptoms that impact patient’s HRQoL.
General impact of migraine
Migraine causes negative effects on various areas of patients’ lives. A cross-sectional study inadults with episodic migraine (EM) or chronic migraine (CM) in Germany, Italy, and the USA
who completed an online survey reported important limitations resulting from migraine inprivate, professional, and social aspects of life, mainly the disruption of daily routines,
significant strain in personal relationships, difficulty caring for children, and missed days ofwork, deadline, or social events 76. In addition, anxiety and frustration were frequently cited as
the emotional consequences of migraine in private/social life and professional life.
A number of studies have also highlighted the substantial impact of migraine on patients’physical health. Patients have remarked on the intensity of pain and the discomfort caused bylight and noise during attacks, and how this has made sleep difficult, and had various othereffects, including bodily pain, tiredness, sweating, and loss of memory 77. Poor sleep quality, inparticular, has been shown to be associated with poor health, significant functional andcognitive impairment, and psychiatric comorbidity 78.

98

The different psychosocial difficulties related to migraine were investigated in a systematic
review of 51 papers reporting clinical trials and observational studies 79 . A total of 34
psychosocial difficulties were identified. The most frequently studied were related to eightareas: emotional problems, decreased vitality and fatigue, pain, difficulties at work, decreased
physical health, decreased mental health, poor social functioning, and increased global
disability. The review found that there were two major determinants of improvements in
psychosocial difficulties: (1) decreased frequency of headaches; and (2) migraine treatments.
Symptomatic medications in the included studies were triptans, which showed evidence for
improving emotional problems and work efficiency. However, the most important determinantsof improvements in psychosocial difficulties were preventatives medications, which showed
evidence for improving emotional problems, work efficiency, global disability, physical health,and mental health 79.
In regard to the economic relationship, research has reported predictive factors for higher total
costs among patients treated for migraine, which included lower health index utility score per
the SF-6D (Short Form 6 Dimension) and lower physical functioning per the PCS (physicalcomposite summary) of the SF-12 (Short-Form Health Survey) 80. Notably, comorbidities were
not statistically significant predictors of being in the highest cost category. Measures associatedwith the frequency of migraine, including preventive eligibility per current or past use of
migraine preventives and preventive eligibility per acute medication overuse, were alsosignificant predictors in the model. This research further demonstrated the importance ofvariables that capture the ictal and interictal disease burden when evaluating economic
outcomes.
Pain
Patients report that pain is the most intense and disabling symptom during a migraine attack.
In a US cross-sectional, real-world analysis, pulsating/throbbing pain and unilateral pain werethe most bothersome symptoms associated with migraine (i.e. impacted lifestyle or work),
being reported as such in >50% of patients, both EM and CM 81. This was despite patientstaking acute and/or preventatives treatment. Pain was also the most commonly self-reported
symptom of migraine in 91.7% of users in an analysis of data from the Migraine Buddy©
smartphone application 82 . Overall, 63.6% of all migraine records from the application(n=28,152 attacks recorded in 3900 individuals) reported a pain intensity of ≥5 (on a scale of
1–10, where 10 = worst pain), which corresponded to an inability of individuals to perform
some of even any activities82. Pain intensity was similar regardless of migraine frequency (see
図 4-10).

99

図 4-10 Pain intensity reported in migraine records captured by the Migraine Buddy©
smartphone application across 17 European countries82

CM, chronic migraine; EM, episodic migraine

Other migraine symptoms
In addition to pain, several other symptoms that are characteristic of migraine attacks havebeen described by patients. The importance of non-pain symptoms has been highlighted byregulatory agencies. Both the European Medicines Agency (EMA) and US Food and Drug
Administration (FDA) emphasize the value of measuring symptoms from the patientperspective and recommend the assessment of migraine-associated symptoms (N/V,
photophobia, phonophobia) when evaluating migraine treatment efficacy 83.
In the Swedish population-based survey of 423 patients with self-considered migraine (45%diagnosed by a physician), symptoms of migraine attacks included photo-/phonophobia (96%of patients), throbbing/aggravation (87%), prodrome (81%), nausea and vomiting (N/V; 79%),
unilateral pain (77%), and aura (44%) (Linde and Dahlof et al, 2004 84 ). Aura was more
frequently reported by patients with a physician’s diagnosis of migraine versus those with selfconsidered migraine (61% vs 29%). The most troublesome symptoms during migraine attacks
were photophobia (in 6% of patients), phonophobia (3%), and nausea (5%). As describedabove, 86% of patients described pain as the most troubling symptom.
Migraine symptoms related to mood and cognition were commonly reported in an analysis ofdata captured by the Migraine Buddy© smartphone application across 17 European countries(n=28,152 attacks in 3900 self-diagnosed individuals). Symptoms that included nausea,
anxiety, confusion, blurred vision, moodiness, or giddiness were reported in 87.3% of
individuals. Symptoms related to environment such as tinnitus, and sensitivity to light, noise,or smell were reported in 85.5% of individuals82. A relatively high rate of anxiety and/or
depression during a migraine attack (as a symptom or trigger) was also reported in 44.8% of
individuals with CM, 40.9% with EM and 8–14 migraine days/month, and 34.7% with EM and
4–7 migraine days/month82.
Health-related quality of life between migraine attacks
Migraine not only adversely affects patient’s HRQoL during an attack, but also has an impact
between attacks 85. Interictal burden has been defined as ‘any loss of health or well-being100attributable to a headache disorder reportedly experienced while ‘headache-free’ 86. There are
numerous reasons why patients with migraine continue to experience the negative impact of
their disease between attacks; for example, in those experiencing frequent attacks, excessive
worry, and fear about when the next attack will strike may occur 86. Avoidance behaviours mightalso occur, with patients trying to limit triggers through lifestyle compromises that may
ultimately diminish pleasure in life. The importance of interictal burden lies in the fact that thisperiod is typically present for more days in the month than the ictal period, especially in thosewith EM86.
The extent of interictal burden in 6455 patients with headache (2959 of which had migraine,
45.8%) was determined in a European cross-sectional survey using modified cluster samplingfrom the adult population (18–65 years of age) in nine countries (the EuroLight Project) 86,87 .
EuroLight involved the administration of a questionnaire that included questions with ‘yes/no’answers regarding elements of headache burden likely to be experienced interictally, as
follows:• Q1. Were you anxious or worried about your next headache episode?
• Q2. Was there anything you could not do or did not do because you wanted to avoid
getting a headache?
• Q3. Did you feel completely free from all headache symptoms?
>70% of patients with migraine gave an ‘adverse response’ to one of the three questions (i.e.
yes to Q1 and Q2, and ‘no’ to Q3), indicating the considerable degree of interictal burden
experienced87. 図 4-11 presents in detail the results to response of each question.
図 4-11 Participants with migraine in the EuroLight Project reporting interictal burden86

Lilly has conducted an analysis to determine if treatment with galcanezumab can reduce
interictal burden, i.e. migraine-related impairment between attacks. A correlation analysis was
subsequently conducted on patient-reported outcomes (PROs) collected in the CGAW study (表4-17) to assess whether the interictal burden was adequately captured in other measures
included in the study 88.
表 4-17 Outcomes included in the correlation analysis
Patient-Reported Outcomes

Outcome Measurement

MIBS-4

Disruptions

Migraine Interictal Burden Scale

to

life

on

days

without101

MIDASMSQ v2.1

Migraine Disability Assessment
Migraine-SpecificQualityofLife
Questionnaire
PGI-S
Patient Global Impression of Severity
GAD-7
Generalized Anxiety Disorder
PHQ-9
Patient Health Questionnaire
WPAI
Work
Productivity
andActivity
Impairment
Additional OutcomesMonthly migraine headache days
Symptom-free headache-free days

headacheDisability due to migraine headache
Functioning in various aspects of life
Severity of overall migraine illness
Anxiety symptoms
Depression symptoms
Impact of migraine on ability to do workand regular activities
Outcome Measurement
Days per month with migraine headacheDays per month with no headache or othermigraine symptoms

Patients treated with galcanezumab experienced statistically significant greater reductions ininterictal burden (LS mean change, -1.8 point reduction on the MIBS-4 scale) compared toplacebo (LS mean change, -0.8 point reduction on the MIBS-4 scale). The Spearman’s Rank
Correlation Coefficients (Rho) were determined for MSQ Total correlation to other PRO outcome
measures. The correlation analysis of the MSQ-total and monthly migraine headache days wasmoderate (-0.52 at month 3), indicating that ‘ictal’ measures, such as migraine headache days,
do not fully capture the HRQoL in migraine. MSQ-Total was most strongly correlated with PHQ9, MIBS, MIDAS and PHQ-9 (図 4-12). This result is not surprising since the MSQ was designed
to measure both ictal and interictal burden of migraine (recall period of 4 weeks)88.
The review of HRQoL data above presents a qualitative and quantitative review of the ‘ictal’and interictal burden of migraine that impacts patient’s HRQoL. Not all can be attributed to achange in monthly frequencies of MHDs. HRQoL, measured with the MSQ, is unlikely to be
explained through a change MHD frequency alone. Contributing factors are also symptoms
associated with the intensity and severity of pain of a migraine headache day, disability causedby migraine headache days, as well as the ictal an interictal burden (see 図 4-12). However,these could be explained by the administration of preventative medication which has beenshown as one of the most important determinants of improvements in psychosocial difficulties,
which evidence showed improved emotional problems, work efficiency, global disability,
physical health, and mental health 89.
図 4-12 Heat maps show correlations between outcomes examined at Months 3, CGAW ITT102Migraine-Specific Quality of Life Questionnaire version 2.1
CGAG, CGAH, CGAI, CGAN and CGAW studies all collected the migraine-specific quality of life
questionnaire (MSQ v2.1), which is a disease specific quality of life instrument. The MigraineSpecific Quality of Life Questionnaire version 2.1 (MSQ v2.1) is a self-administered healthstatus instrument that was developed to address the physical and emotional impact on
functioning that is of specific concern to individuals suffering from migraine headaches. The
instrument consists of 14 items that address 3 domains: (1) Role Function-Restrictive; (2) Role
Function-Preventive; and (3) Emotional Function 90 . The restrictive domain specificallymeasures disability as related to the impact on performance of normal activities, with thepreventive domain addressing complete functional impairment and the emotional domain
assessing the feelings related to disabling monthly migraine headache days. Responses are
given using a 6-point Likert-type scale, ranging from “none of the time” to “all of the time.”
Raw scores for each domain are computed as a sum of item responses, with the collective sum
providing a total raw score that is then converted to a 0 to 100 scale, with higher scoresindicating a better health status, and a positive change in scores reflecting functional
improvement 91,92. The instrument was designed with a 4-week recall period and is considered
reliable, valid, and sensitive to change in functional impairment due to migraine90,93.
The EQ-5D-5L quality-of-life instrument was administered in the CGAW study only, which
excluded patients with one prior preventive treatment failure. Despite this limiting factor, thetrial results from CGAW for MSQ v2.1 and EQ-5D-5L (mapped to the EQ-5D-3L) were compared
to assess which instrument produced reliable results for the economic analysis. Past NICE
appraisals for onabotulinumtoxinA, erenumab, and fremanezumab (NICE, 2012; 2019a and b)
for preventing migraine have preferred the MSQ over the EQ-5D, stating that the EQ-5D may
not be sensitive and does not capture all the important symptoms of disease that impact
patient’s quality-of-life. A reason for this may be the insufficient recall period of “today” for the
EQ-5D in migraine and the frequency of administration in clinical trials.
The EQ-5D-5L instrument collects HRQoL information at a single point in time, as it asks
patients to complete the questionnaire based on how they feel “today”. In addition, the103instrument was administered at baseline and once again at study visit at 3 months at the endof the double-blind period of CGAW. Patients who experienced a migraine were unlikely toattend a study visit on that specific day. Given the recall period being today, it is therefore
more likely to capture utility results similar to that of the population norm (see 図 4-13). This
may explain the differing results observed between the two instruments, since patients wereasked to complete the questionnaire when they may not have been experiencing a migraine
attack.
In contrast, the MSQ was administered monthly throughout the randomized phases of CGAG,
CGAH, CGAI, CGAN and CGAW. The MSQ has a 4-week recall period; therefore, it may havethe ability to capture interictal burden, or impairment between attacks 94, as well as capturing
more granular changes in HRQoL due to attacks in the preceding 4-weeks, which the EQ-5D is
not able to do given the short “one point in time” recall period.
A visual assessment of the individual patient utility values, the observed mean, and theestimated mean utility values as a function of Migraine Headache Days from CGAW are shownin 図 4-13. This shows that there is minimal change in utility when measured using the EQ5D compared to the MSQ with increasing monthly migraine headache days.
図 4-13 Utilities derived f rom the MSQ and f rom the EQ-5D-3L estimates, f or each number ofMigraine Headache Days, at Month 3 using CGAW data

Utilities derived from the Migraine Specific Quality of Life instrument
A literature review was conducted during the model development; however the search yielded
no results related to utility data while on galcanezumab treatment. As such, MSQ utility data,collected in the galcanezumab clinical trial program, were mapped to the EQ-5D-3L to estimate
the quality of life of patients for the populations indicated in the analytical framework provided
by C2H, for the purpose of the Japanese economic model. Using trial-specific information

104

allows to more accurately depict the impact of small changes in migraine headache days on
HRQoL and to capture the treatment specific effect of galcanezumab over placebo (‘BSC’) on
HRQoL.
前述の通り片頭痛の発作が QOL 値に与える影響を EQ-5D により正しく評価することはできない。このため企業
は、以下のようなプロセスにより MHD を UK のタリフをもとにした EQ-5D-3L のスコアに換算する回帰式を作成し、使用した。
1. 片頭痛の疾患特異的尺度である MSQ を EQ-5D-3L にマッピングし、換算するアルゴリズムを提供する(Gillard et al. 2012 95)を用い、CGAN、CGAH、CGAG、CGAI、CGAW 試験により評価された MSQ から
EQ-5D-3L(UK タリフ)による QOL 値を求めた。
2. CGAN、CGAH、CGAG、CGAI、CGAW 試験において評価された MHD を用い、単回帰分析により、MHD
から 1．で求めた QOL 値を推定する回帰式を作成した。
上記のプロセスは、Gillard et al.にて提供されたアルゴリズムを使用しているが、これは UK のタリフをもとにしている。日本のタリフを用いた同様の研究はないため、日本のタリフを用いた同様の回帰式を作成することはできない。
実現可能性の制約からやむを得ず UK のタリフを用いる必要があったが、この方法により片頭痛の疾患特異的尺度を用いた評価により MHD を QOL 値に換算することができるというメリットがあり、このメリットはタリフの 差異によるデメリットを上回ると考えられた。
上記方法の詳細について以下に説明する。
Following a technical document from the NICE Decision Support Unit, which states thatmapping can be used to predict EQ-5D data 96 , utilities were derived using a previously
independently derived and published mapping algorithm by Gillard and colleagues 201295 . The
mapping function was derived based on data from the International Burden of Migraine Study(IBMS). The IBMS study is a global, cross-sectional web-based survey, which enrolled patientsfrom Australia, Canada, France, Germany, Italy, Spain, United Kingdom, Taiwan, Brazil and US
and was conducted from February to April 2009. Patients were at least 18 years of age who
experienced headaches over the last 3 months and met the ICHD-II criteria. The total sample
consisted of ~10,000 patients. The survey collected information using the MSQ v2.1
questionnaire as well as the EQ-5D-3l. Based on this dataset, Gillard and colleagues (2012)95
estimated a function, which allows to map the results of the Migraine-Specific Quality-of-Life
Questionnaire (MSQ) domain scores collected at each month for episodic and chronic migraine
patients to the EQ-5D-3l using the UK country-specific utility tariffs. Ordinary least squared
regression models were constructed to estimate EQ-5D questionnaire utility values from MSQ
v2.1 domain scores. The UK valuation set for raw EQ-5D questionnaire scores were used as
the dependent variable, while the disease specific scores of the MSQ (RP, RR, EF) wereconsidered as independent variables resulting in the following model:
EQ-5D questionnaire = α + β1 MSQ-RP + β2 MSQ-RR + β3 MSQ-EF + error.
Gillard and colleagues 201295 also derived an alternative regression model considering type of
migraine with additional covariates, which was stated to be the preferred model. However,some of the covariates were not clearly defined. For example, they considered “headache
medication” as a covariate without specifying what specifically counted as headache medication.
Therefore, it was decided to use the model without covariates as highlighted in 図 4-14.
No other published mapping function allowing for the inclusion of alternative country-specificutility sets were identified in the literature. The following steps were undertaken to derive theutilities for the Japanese cost-effectiveness model.

105図 4-14 Mapping steps f rom MSQ to EQ-5D-3l

f1 refers to the Model 1 (𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈^UK=α + β1 MSQ-RP+ β2 MSQ-RR+ β3 MSQ-EF + error)
Utility^UK is the health index score with the EQ-5D UK value sets applied
Utility values were estimated for each migraine headache day frequency ranging from 0 to 30
to match the patient population with 1 or 2 prior preventive treatment failures and for those
who have more than 3 prior preventive treatment failures for baseline, representing the healthstate ‘off treatment’ and month 1-3, representing the health state ‘on-treatment’ using the
mapping function developed by Gillard et al 201295 . The utility models specified by Gillard etal 201295 were used to further investigate whether the treatment effect variable should be
included into the regression.
A linear model was used to estimate the utilities associated with the monthly migraine
headache days at baseline using the observations for the subpopulations of interest in CGAG,
CGAH, CGAI, CGAN and CGAW. Independently, migraine headache days as observed in month
1 to 3 were modeled using a mixed model for repeated measures with migraine headache days
and study treatment as covariates and an unstructured variance covariance matrix. This modelallowed to account for the full extent of the longitudinal data structure as highlighted in Griffiths
2017 97. The observations and predictions for the patient population with a history of 1 or 2prior preventive treatments or those with at least 3 prior preventive treatments is presented
in 図 4-15.

106図 4-15 Mixed model f or repeated measures to predict utilities considering observations atmonth 1, 2 and 3

Source: prd/ly2951742/hta_submission/output/shared/hta_japan/utilities_m123_Gillard_dtt3.docx,
prd/ly2951742/hta_submission/output/shared/hta_japan/utilities_m123_Gillard_failed1or2.docx

Considering the statistically significant covariate ‘study treatment’, differential utilities values
for the analysis of galcanezumab compared to best supportive care (BSC) were applied, taking
account of the observed treatment effect in the clinical trials. Doing so, can account for
additional aspects of migraine which may impact HRQoL not captured solely through thechange in the frequency of migraine headache days (see also section 3.2, 表 4-18). The
treatment effect is statistically significant across both patient populations of interest using
CGAG, CGAH, CGAI, CGAN and CGAW. For the comparison to propranolol and valproic acid,the utility values associated with galcanezumab for the health state ‘on-treatment’ are applied
for both galcanezumab and either propranolol or valproic acid depending on the comparison.
表 4-18 Regression parameters of the mixed model considering month 1 to 3 using trial dataf rom CGAG, CGAH, CGAI, CGAN and CGAW
Failed 1 or 2
preventatives

Failed 1 or 2
preventatives Pr(>|t|)(Intercept)

0.76960<0.0001

Failed ≥3
prior
preventatives
0.74830

MHD
Treatment
Observation
s
AIC
BIC

-0.01182
0.02687<0.0001<0.01-0.01242
0.057712408-4143.2-4114.2

1436

Failed ≥3
prior
preventatives Pr(>|t|)<0.0001<0.0001<0.001-2305.6-2279.3

Source:/lillyce/prd/ly2951742/hta_submission/output/shared/hta_japan/utilities_m123_Gillard_failed1or2.docx;/lillyce/prd/ly2951742/hta_submission/output/shared/hta_japan/utilities_m123_Gillard_dtt3.docx

Differences in HRQoL are therefore captured in the cost-effectiveness model throughdifferences in the frequency in migraine headache days and the treatment applied to the modeland subsequently whether patients are in the ‘on-treatment’ or ‘off-treatment’ health state.
The ‘on’-and ‘off-treatment’ utilities were selected for use in the economic model using
migraine headache days and treatment effect as the only covariates in the model (see 表 4-

107

19).
表 4-19 Alternative utility values used f or the comparison to BSC, propranolol or valproic acidwith base case settings
Health-StateFirst-cycle
Responder
Discontinuationdue
tononresponse (3-monthassessment)
Discontinuation
due to All-cause(long-term,
percycle)

Base case
Initiate treatment

Galcanezumab
Off-treatment
GalcanezumabComparator
Off-treatment
BSC

Galcanezumab

Galcanezumab

Patients return to baselinemigraine headache days

Off-treatment

Off-treatment

Patients return to baselinemigraine headache days

Off-treatment

Off-treatment

vs BSCvs propranolol/valproic acid

表 4-20 presents the number of observations from CGAG, CGAH, CGAI, CGAN and CGAW andthe predicted utility values as a function of number of migraine headache days and treatment
covariate for the population with a history of 1 or 2 prior preventive treatment(s) andseparately for those patients with a history of at least 3 prior preventive treatments. No utilities
were predicted for the subpopulation of patients who only use a 2nd line preventive treatment
or only use a 3rd line preventive treatment due to the limited number of observations, which
will impact the precision of estimates. Hence, for those two subpopulations, the same utilities
are applied as for the patients with a treatment history of 1 or 2 prior preventive treatments.

108表 4-20 Trial utilities f or subgroup of patients f ailed 1 or 2 preventive treatments or at least 3 preventive treatments EQ-5D-3L values (mapped f rom MSQ)
No.
of
MHD

Population with a history of 1 or 2 prior preventive
treatments
Baseline

Galcanezumab

Population with a history of at least 3 prior preventive
treatments

BSC

Baseline

Utility value

N

Utility
value

N

58

0.796526

0.7696

BSC

0

NA

Utilityvalue
0.78741NA0.770049

0.7847370.7578NA

0.7936

70.73592NA0.752651

0.772863

0.7460NA

0.734735

0.7812130.72353NA0.735179

0.761065

0.7341NA

0.718037

0.7688210.71104310.717771

0.722390.7014430.756330

0.69865370.700363

0.737476

0.7105130.6847390.743923

0.68626

390.682960

0.7256900.698713

0.668048

0.731533

0.6738758

0.665525

0.7137670.6869130.651325

0.719125

0.6614857

0.6480670.7019860.675032

0.6346410.706733

0.64899630.630653

0.6901105

0.663229

0.617938

0.694239

0.636510560.613245

0.6783110

0.651439

0.601237

0.681850

0.624111

67

0.595834

0.666568

0.639633

0.584529

0.669447

0.611712

48

0.578434

0.654679

0.627829

0.5679190.657039

0.599313

420.560927

0.642889

0.6159220.551226

0.644635

0.58681453

0.5435280.604136

0.534521

0.632133

0.574415

25

0.5261170.6192420.592331

0.517860.619723

0.562016

24

0.5087200.607459

0.5805160.5011170.607334

0.549617270.491211

0.595538

0.5687

11

0.484415

0.5949370.537218

29

0.4738150.583737

0.556824

0.4677

6

0.582546

0.524719260.456410

0.571933

0.5450190.4510120.5700340.512320

28

0.4390120.5601170.533223

0.434313

0.557628

0.499921

190.421614

0.521418

0.417715

0.545224

0.487522200.404112

0.536426

0.5096160.40107

0.532824

0.475123

17

0.3867

50.524618

0.4977110.384350.520414

0.462624

170.369360.5128220.4859150.367690.5079230.450225

140.351990.501013

0.4741100.350940.495530

0.437826

140.3345

50.489221

0.46237

0.3342

4

0.483111

0.4254

N

N

Galcanezumab

0.7492

0.63100.5483

91

54

23

N

Utilityvalue

N

Utilityvalue

NA

Utilityvalue
0.7681410.806040.74830.7514

28

109

27

13

0.3170328

100.29963

0.465529

70.282240.453730

NA0.264870.44190.47730.4505120.31756

140.438690.300830.458390.400580.426840.284130.44586

0.3881210.4150NA

0.267540.4334120.3757130.4707130.4130Source:/lillyce/prd/ly2951742/hta_submission/output/shared/hta_japan/utilities_m123_Gillard_failed1or2.docx;/lillyce/prd/ly2951742/hta_submission/output/shared/hta_japan/utilities_m123_Gillard_dtt3.docx;
lillyce/prd/ly2951742/hta_submission/output/shared/hta_japan/utilities_baseline_Gillard_dtt3.docx;
lillyce/prd/ly2951742/hta_submission/output/shared/hta_japan/utilities_baseline_Gillard_failed1or2.docx

1104.2.3 費用のパラメータの詳細
4.2.3.1 Cost and resource use
The cost effectiveness model considers the resource use and cost of emergency room
department (outpatient visits), hospitalisations (DPC service), physician visits, administration
costs and acute medications. Costs and resource use relating to each component are describedin subsequent sections.
4.2.3.2 Drug acquisition costs
Drug acquisition costs were calculated by combining the cost per unit and the required numberof units per cycle. The drug costs per pack, dosing and frequency of dose administration isshown in 表 4-21. Drug costs were sourced from the NHI price list 98. If available branded drug
prices were used. Allowing a unit per cycle costing gives detailed reflections of the annual costs
associated with each treatment. The most relevant comparators are propranolol, valproic acid(sensitivity analysis only) and BSC for episodic and chronic migraine patients. BSC comprisesof self-administration of acute medications and resource use associated with the specific meanchange migraine headache days. BSC was not associated with additional costs as both
galcanezumab and active comparators are assumed to be given with the same acutemedication received in BSC. The daily dose for propranolol and valproic acid was informed by
the analysis of the local claims database (JMDC 2021 (Appendix 4-1)).
表 4-21 Drug costs, dosing and f requency of dose administration
Propranolol

mg/unit

Galcanezumab
120mg
120

10

100

Unit cost¥45,165a¥11.60a¥10.10a

240mg for first
injectionb
120mgb

N/A

N/A

21.59mgc

334.76mgc

Administration/cycle

1

30

30

Frequency (day)

30

30

30

Loading dose
Dose (mg)

Dose/cycle
Source120mg
a

NHI price list (2021) 98b
PMDA, 20211

Valproic Acid

647.70mg
a

NHI price list (2021)98,c
JMDC 2021 (Appendix 4-1)

10042.80mg
a

NHI price list (2021)98,c
JMDC 2021 (Appendix 4-1)

The model allows for a loading dose and different dosing cycles based on the productcharacteristics for the respective treatment. For the loading dose of galcanezumab, this isapplied in the first cycle of treatment and is applied in addition to the maintenance dose.

1114.2.3.3 Resource use and unit costs
Healthcare professional use
The model considers resource use, like healthcare professional use by each migraine
headache day, which was informed from an analysis conducted by Kikui et al 2020 50
using data from the Japanese National Health and Wellness Survey (NHWS) collected
in 2017. The study enrolled a sample of the general Japanese population, which was
divided into a migraine cohort defined by the ICHD-3 criteria with at least 4 migraine
headache days (N=378) and a matched non-migraine control cohort (N=1,512).
The study reported 6-month average medical resource use for the number of physician
visits (migraine cohort: 7.23; non-migraine cohort: 3.96), emergency room visits(migraine cohort: 0.03; non-migraine cohort: 0.01) and hospitalisations (migraine
cohort: 0.80; non-migraine cohort: 0.49). Considering that not all medical resource
use in the migraine cohort may be attributable to migraine, it was assumed that the
surplus of the difference between the migraine and matched non-migraine cohort isan appropriate proxy for the medical resource use associated with migraine. This
results in 3.27 physician visits/6 months, 0.31 hospitalisation/6 months and 0.02
emergency room visits/6 months. The migraine patients had on average 46 migraine
episodes over a 6-month period resulting in 7.67 mean monthly migraine headachedays assuming that an episode equals a day. Medical resource use per migraine
headache day was estimated by dividing the 6-month average use by the mean
number of migraine headache days reported over a 6-month period by patients. The
unit costs for each resource category (emergency department visits, hospitalizations,and physician visits and pharmacy dispensing fee) are calculated using Instruction on
medical care fee points (April 2021). 表 4-22 shows the costs used per resource andthe associated use per migraine headache day.
表 4-22 Resource use and costs
Emergency roomuse (outpatient)

Hospitalisation^(DPC service)

Physician visit*

Cost¥34,165¥170,817¥3,130

Average use per migraine
day

0.000430.00674

0.07109^assuming 4 days in hospital, *Physician visit (including tests etc is considered as an emergency situation but not using
emergency room)

Using published medical resource use by Kikui et al 202050 had some limitations: (i)it was not specific to the target population who had a history of either 1 or 2 priorpreventive treatments or ≥3 prior preventative treatments or by subtype of migraine,(ii) it is based on survey information not medical records and self-reported migraine.
However, the strengths of the approach taken by Kikui et al 2020 50 is that it does
allow to estimate the rate of medical resource use associated with each migraine
headache day due to the inclusion of the migraine and matched non-migraine cohort.
Being able to calculate the resource use by number of migraine headache days isaligned with the underlying model structure. Moreover, the evidence for healthcare
professional resource use was based on local Japanese data from the general
population increasing the transposability of the results.
In addition to the healthcare professional resource use depending by migraine
headache day frequency ( 表 4-21), an additional physician consultation andprescription fee is assumed for the administration of galcanezumab every month at a
cost of ¥3,330/visit and for propranolol and valproic acid every other month at a costof ¥3,990/visit.
Acute medication use per migraine headache day frequency
The economic analysis also captures acute medication use per migraine headache day112frequency by applying a binomial distribution to predict the frequency of acutemedication use with triptans, acetaminophen (paracetamol and containing products)
and NSAIDs, with each migraine headache day frequency. The number of monthly
migraine headache days with use of triptans or NSAIDs/aspirin or
acetaminophen/paracetamol were collected daily via an eDiary in CGAG, CGAH, CGAI,
CGAN and CGAW. For this analysis all observations at month 3 were considered forthe subgroups of patients with aI. history of 1 or 2 preventive treatment failures (ie. 2nd or 3rd line preventive
treatment)
II. history of at least 3 prior preventive treatment failures (ie. ≥4th line preventive
treatment)
No separate analysis was performed for those patients who have a history of 1 failure(ie. 2nd line) or 2 failures (ie. 3rd line) due to lower number of observations given thesmaller sample and subsequently the greater uncertainty around the predictions. The
results for population (I) were therefore also applied for those patients who have ahistory of 1 failure (ie. 2nd line) or 2 failures (ie. 3rd line). Although several distributions
were tested to predict the acute medication use by frequency of migraine headachedays, only the binomial distribution predicted no use of acute medication when
patients experienced no migraine headache days. Given the definition of this variable
and clinical plausibility, this distribution was chosen.
The weighted cost per day was based on the mean average daily dose informed by
the JMDC analysis (Appendix 4-2), the pack size, local uptake and branded drug cost,
if available, in line with the Japanese HTA guideline49. This results in daily costs fortriptans of ¥933.13, for acetaminophen/paracetamol of ¥23.04 and for NSAID/Aspirinof ¥23.38.

113

A summary of frequencies of resource use by category, excluding administration cost,
and the resultant total management costs by monthly migraine headache day
frequency is provided in 表 4-23. The same number of healthcare professional visits
was assumed for patients irrespective of line of treatment, while acute medication use
was estimated for the patients with a history of 1 or 2 prior preventive treatments or
at least 3 prior preventive treatments resulting in slightly different total management
costs across the range of possible number of migraine headache day frequency,
irrespective of treatment, as seen in 表 4-23.

114

表 4-23 Summary of medical resource use f requency and total cost by monthly migraine headache days
No. ofMHD

PhysicianvisitsHospitalisation (DPC
service)

AE visit(outpatient
)

0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30

0.00000.07110.14220.21330.28430.35540.42650.4976
0.56870.63980.71090.78200.85300.92410.9952
1.0663
1.13741.20851.27961.35071.42171.49281.56391.63501.70611.7772
1.8483
1.91931.99042.06152.13260.00000.05170.10330.15500.20670.25830.31000.36170.41330.46500.51670.56830.62000.67170.72330.77500.82670.87830.93000.98171.03331.08501.13671.18831.24001.29171.3433
1.39501.44671.49831.55000.00000.00330.00670.01000.01330.01670.02000.02330.02670.03000.03330.03670.04000.04330.04670.05000.05330.05670.06000.06330.06670.07000.07330.07670.08000.08330.08670.09000.0933
0.09670.1000

Failed 1 or 2 prior treatments
Paracetamo
l use
0.00
0.18
0.36
0.54
0.72
0.90
1.08
1.27
1.45
1.64
1.82
2.01
2.20
2.39
2.58
2.77
2.96
3.15
3.35
3.54
3.74
3.93
4.13
4.33
4.52
4.72
4.92
5.13
5.33
5.53
5.74

NSAID
Use
0.00
0.46
0.91
1.35
1.79
2.21
2.63
3.04
3.45
3.84
4.23
4.61
4.98
5.35
5.70
6.06
6.40
6.73
7.06
7.38
7.69
8.00
8.30
8.59
8.88
9.15
9.42
9.69
9.94
10.19
10.44

Triptan
use
0.00
0.56
1.11
1.65
2.18
2.70
3.21
3.72
4.21
4.70
5.17
5.64
6.09
6.54
6.98
7.41
7.83
8.24
8.64
9.04
9.42
9.79
10.16
10.51
10.86
11.20
11.53
11.85
12.16
12.46
12.76

Failed at least 3 prior treatments
Total
costs
¥0
¥9,733¥19,456¥29,168¥38,871¥48,564¥58,246¥67,928¥77,591¥87,253¥96,895¥106,537¥116,158¥125,780¥135,392¥144,994¥154,585¥164,166¥173,738¥183,309¥192,860¥202,401¥211,942¥221,463¥230,984¥240,494¥249,995¥259,486¥268,966¥278,436¥287,907

Paracetamo
l use
0.00
0.07
0.15
0.23
0.31
0.41
0.51
0.61
0.72
0.84
0.97
1.10
1.24
1.39
1.55
1.72
1.90
2.08
2.28
2.49
2.70
2.93
3.17
3.43
3.69
3.97
4.26
4.57
4.89
5.22
5.57

NSAID
Use
0.00
0.33
0.68
1.03
1.39
1.76
2.13
2.52
2.91
3.31
3.72
4.14
4.57
5.01
5.46
5.91
6.38
6.85
7.33
7.83
8.33
8.84
9.36
9.89
10.42
10.97
11.53
12.10
12.67
13.26
13.85

Triptan
use
0.00
0.58
1.16
1.74
2.31
2.88
3.45
4.01
4.56
5.12
5.67
6.21
6.75
7.29
7.82
8.35
8.88
9.40
9.92
10.43
10.94
11.45
11.95
12.45
12.94
13.43
13.92
14.40
14.87
15.35
15.82

Total
costs
¥0
¥9,747¥19,495¥29,243¥38,981¥48,720¥58,459¥68,189¥77,909¥87,639¥97,360¥107,071¥116,782¥126,494¥136,197¥145,899¥155,603¥165,296¥174,991¥184,675¥194,360¥204,046¥213,722¥223,399¥233,066¥242,734¥252,402¥262,061¥271,711¥281,371¥291,021115

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
費用対効果評価専門組織で決定された分析枠組みに基づき、4 つの対象集団に対して下記 の通り 分析を実施した。
（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛患者■ 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）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性片頭痛患者■ 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）（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者■ 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）（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者■ 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
分析対象集団ごとの分析の結果および費用の内訳は下記の通りである。
（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛患者･ 分析結果の要約
効果 (QALY)

増分効果 (QALY)

費用 (円)

増分費用(円)

ICER(円/QALY)

12.5700.230¥5,500,826¥1,396,932¥6,077,875

12.340/¥4,103,894//

評価対象技術
Galcanezumab
120mg

比較対照技術
Propranolol･ 費用の内訳の詳細
評価対象技術：
Galcanezumab 120mg

比較対照技術：
Propranolol

予防治療薬剤費¥1,522,571¥6,387

外来診察費用

¥105,599¥16,958

救急・入院費用¥2,813,546¥2,965,757

急性期治療薬剤費¥1,059,111¥1,114,791

費用（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性片頭痛患者･ 分析結果の要約
効果 (QALY)

増分効果 (QALY)

費用 (円)

増分費用(円)

ICER(円/QALY)

116

評価対象技術
Galcanezuma
b 120mg

比較対照技術
Propranolol

9.398

0.509

¥9,879,533¥1,371,145¥2,691,706

8.889

/

¥8,508,388//･ 費用の内訳の詳細
評価対象技術：
Galcanezumab 120mg

比較対照技術:
Propranolol

予防治療薬剤費¥1,701,604¥6,553

外来診察費用¥118,799¥17,401

救急・入院費用¥6,047,006¥6,372,062

急性期治療薬剤費¥2,012,124¥2,112,371

費用（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者･ 分析結果の要約
効果 (QALY)

増分効果 (QALY)

費用 (円)

増分費用(円)

ICER(円/QALY)

12.1580.381¥5,539,801¥1,087,066¥2,850,240

11.777/¥4,452,735//

評価対象技術
Galcanezuma
b 120mg

比較対照技術BSC･ 費用の内訳の詳細
評価対象技術：

比較対照技術:

Galcanezumab 120mg

BSC

予防治療薬剤費¥1,376,635¥0

外来診察費用¥94,839¥0

救急・入院費用¥2,882,664¥3,155,769

急性期治療薬剤費¥1,185,662¥1,296,966

費用（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者･ 分析結果の要約
効果 (QALY)

増分効果 (QALY)

費用 (円)

増分費用(円)

ICER(円/QALY)

9.439

0.735

¥9,853,551¥1,059,682¥1,441,739

8.704

/

¥8,793,870//

評価対象技術
Galcanezuma
b 120mg

比較対照技術BSC･ 費用の内訳の詳細
評価対象技術：

比較対照技術:

Galcanezumab 120mg

BSC

予防治療薬剤費¥1,699,115¥0

外来診察費用¥118,615¥0

救急・入院費用¥5,758,503¥6,304,054

費用

117

急性期治療薬剤費¥2,277,318¥2,489,815

5.1.2 感度分析
5.1.2.1 専門組織の指示に基づく感度分析
本剤の費用対効果評価にかかる分析枠組みの中で指示された感度分析としてのシナリオ分析を行 った。
それぞれの対象集団と比較対照技術は以下の通りである。
1. 片頭痛予防薬の２剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のため使用できな
い反復性片頭痛患者
2. 片頭痛予防薬の２剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のため使用できない慢性片頭痛患者
3. 片頭痛予防薬の３剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のため使用できな
い反復性片頭痛患者
4. 片頭痛予防薬の３剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のため使用できない慢性片頭痛患者
・分析対象集団1および2:既存の片頭痛予防薬（プロプラノロール、バルプロ酸）のうち、当該集 団に対して禁忌ではないもの＝基本分析をプロプラノロールで実施したので、バルプロ酸を選択
・分析対象集団 3 および 4: Best Supportive Care
結果を以下に示す。
1

片頭痛予防薬の２剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のため使 用できない反復性片頭痛患者
効果 (QALY)

増分効果(QALY)

費用 (円)

増分費用(円)

ICER(円/QALY)

Galcanezuma
b 120mg

12.5640.242¥5,572,347¥1,422,129¥5,882,887

Valproic Acid

12.323/¥4,150,219

/

/

2

片頭痛予防薬の２剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のため使 用できない慢性片頭痛患者
効果 (QALY)

増分効果(QALY)

費用 (円)

増分費用(円)

ICER(円/QALY)

Galcanezuma
b 120mg

9.395

0.572

¥10,047,701¥1,465,894¥2,562,916

Valproic Acid

8.823

/

¥8,581,806

/

/

3

片頭痛予防薬の３剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のため使 用できない反復性片頭痛患者
効果 (QALY)

増分効果(QALY)

費用 (円)

増分費用(円)

ICER(円/QALY)

Galcanezuma
b 120mg12.6740.324¥5,218,126¥1,216,247¥3,751,390

BSC

12.349/¥4,001,879

/

/

4

片頭痛予防薬の３剤目の治療において既存の片頭痛予防薬が禁忌又は副作用のため使 用できない慢性片頭痛患者

118

効果 (QALY)

増分効果(QALY)

費用 (円)

増分費用(円)

ICER(円/QALY)

Galcanezuma
b 120mg

9.524

0.604

¥9,490,615¥1,086,106¥1,798,947

BSC

8.920

/

¥8,404,509//

本剤の費用対効果分析において、片頭痛予防薬の 2 剤目の治療の対照薬としてプロプラノロール について記述したが、プロプラノロールの添付文書上の禁忌疾患として以下の疾患が該当する。
 気管支喘息，気管支痙攣のおそれのある患者，糖尿病性ケトアシドーシス，代謝性アシ ド ーシ スのある患者，高度又は症状を呈する徐脈，房室ブロッ ク（II， III 度），洞房ブロッ ク，洞不全 症候
群のある患者、心原性ショックの患者，肺高血圧による右心不全のある患者， うっ血性心不 全のある患者，低血圧症の患者，長期間絶食状態の患者，重度の末梢循環障害のある患者， 未治療の褐色細胞腫の患者，リザトリプタン安息香酸塩を投与中の患者発生頻度を勘案した上で、気管支喘息，低血圧症，および徐脈について片頭痛患者における 併存疾患として罹患している割合を株式会社 JMDC の健保ベースのレセプトデータより 2005 年から 2 021 年の期間で検討した。その結果を以下の表に示す。
ICD10 コード

気管支喘息
低血圧症
徐脈

片頭痛

禁忌疾患

G43
G43
G43

J45
I95
R001

禁忌疾患該当患者数
2,670
561
30
総計

出典： JDM-PV

片頭痛患者（n=35,116）にお
ける割合
7.6%
1.6%
0.08%
9.3%

片頭痛予防薬の 2 剤目の治療において、プロプラノロールの禁忌疾患のためにバルプロ酸を使用 する
患者は 9.3%である。
5.1.2.2 Deterministic sensitivity analyses (DSA)
基本分析に対する感度分析の結果を述べる。
Episodic Migraine population with a history of treatment failure to 1 or
2 prior preventive migraine treatments (Propranolol comparison)
The result of the deterministic sensitivity analysis (DSA) in the episodic migraine
patient population with a history of 1 or 2 prior preventive treatments (ie. 2nd or 3rdline preventive treatment) comparing galcanezumab to propranolol is presented in 図
5-1 and 表 5-1. The most impactful parameters are the utility treatment effectobserved in the clinical trial program of galcanezumab, followed by the mean change
from baseline in monthly migraine headache days for galcanezumab and discountrates for QALYs. All upper and lower bound ICERs remain below the ¥7,500,000
willingness to pay threshold. 表 5-1 provides a comprehensive overview of the resultsof various variables tested in the DSA in the episodic migraine patient population witha history of 1 or 2 prior preventive treatments comparing galcanezumab to propranolol.
•119図 5-1 DSA in the episodic migraine patient population with a history of 1 or 2 priorpreventive treatments (propranolol comparison)120

表 5-1 Detailed results of the DSA f or the episodic migraine patient population with a history of 1 or 2 prior preventive treatments(Propranolol comparison)
Parameter

Range

Base caseDiscount rate QALY
Discount rate - Cost
Baseline - Age
Baseline - Gender
Baseline - MHD
GMB response rate
(50%)

Galcanezumab

Propranolol

Incremental

Cost

QALY

Cost

QALY

Cost

QALY

ICER

Δ ICERin %¥5,500,826

12.5698¥4,103,894

12.3400¥1,396,932

0.2298¥6,077,875

LB (0.00%)¥5,500,826

15.6860¥4,103,894

15.4295¥1,396,932

0.2565¥5,446,813-10.38%UB (4.00%)¥5,500,826

10.3157¥4,103,894

10.1075¥1,396,932

0.2081¥6,712,299

10.44%

LB (0.00%)¥6,651,384

12.5698¥5,136,269

12.3400¥1,515,115

0.2298¥6,592,073

8.46%

UB (4.00%)¥4,658,322

12.5698¥3,357,967

12.3400¥1,300,355

0.2298¥5,657,680-6.91%

LB (42.55)¥5,507,190

12.5873¥4,109,698

12.3573¥1,397,492

0.2300¥6,076,977-0.01%UB (44.11)¥5,494,025

12.5511¥4,097,705

12.3214¥1,396,320

0.2297¥6,078,846

0.02%

LB (85.45%)¥5,498,529

12.5634¥4,101,770

12.3336¥1,396,759

0.2298¥6,078,150

0.00%

UB (90.50)¥5,502,953

12.5757¥4,105,861

12.3458¥1,397,092

0.2299¥6,077,621

0.00%

LB (8.84)¥5,408,162

12.6372¥4,011,437

12.4096¥1,396,725

0.2276¥6,135,705

0.95%-0.93%UB (9.26)¥5,593,398

12.5024¥4,196,233

12.2703¥1,397,165

0.2320¥6,021,333

LB (39.25%)¥5,281,318

12.5260¥4,103,894

12.3400¥1,177,424

0.1861¥6,327,598

4.11%

UB (56.89%)¥5,721,630

12.6138¥4,103,894

12.3400¥1,617,737

0.2739¥5,907,179-2.81%

Propranolol
response rate(50%)

LB (48.87%)¥5,500,826

12.5698¥4,104,170

12.3379¥1,396,656

0.2319¥6,023,080-0.90%UB (69.41%)¥5,500,826

12.5698¥4,103,627

12.3419¥1,397,199

0.2279¥6,131,768

0.89%

GMB - mean MHD
change

LB (-4.07)¥5,467,479

12.5881¥4,103,894

12.3400¥1,363,586

0.2481¥5,495,217-9.59%UB (-3.05)¥5,534,241

12.5515¥4,103,894

12.3400¥1,430,347

0.2115¥6,762,258

11.26%

LB (-3.29)¥5,500,826

12.5698¥4,094,840

12.3446¥1,405,986

0.2252¥6,242,283

2.71%

UB (-1.57)¥5,500,826

12.5698¥4,112,904

12.3354¥1,387,922

0.2344¥5,920,211-2.59%

LB (¥10)¥5,500,826

12.5698¥4,102,843

12.3400¥1,397,983

0.2298¥6,082,446

0.08%

UB (¥14)¥5,500,826

12.5698¥4,104,944

12.3400¥1,395,882

0.2298¥6,073,304-0.08%

LB (¥2,634)¥5,429,317

12.5698¥4,028,516

12.3400¥1,400,801

0.2298¥6,094,707

0.28%-0.30%

Propranolol - mean
MHD change
Propranolol costs
Costs for physician
visitsCost forhospitalisation
Cost for A&E visit
Use per migraine
day - physician
visitsUse per migraine

UB (¥3,662)¥5,577,458

12.5698¥4,184,672

12.3400¥1,392,786

0.2298¥6,059,837

LB (¥143,724)¥5,130,860

12.5698¥3,713,913

12.3400¥1,416,947

0.2298¥6,164,958

1.43%

UB (¥199,851)¥5,897,299

12.5698¥4,521,816

12.3400¥1,375,483

0.2298¥5,984,553-1.54%

LB (¥28,746)¥5,496,052

12.5698¥4,098,861

12.3400¥1,397,190

0.2298¥6,078,999

0.02%

UB (¥39,972)¥5,505,942

12.5698¥4,109,286

12.3400¥1,396,655

0.2298¥6,076,671-0.02%

LB (0.060)¥5,429,317

12.5698¥4,028,516

12.3400¥1,400,801

0.2298¥6,094,707

0.28%

UB (0.083)¥5,577,458

12.5698¥4,184,672

12.3400¥1,392,786

0.2298¥6,059,837-0.30%

LB (0.006)¥5,130,860

12.5698¥3,713,913

12.3400¥1,416,947

0.2298¥6,164,958

1.43%

121

day - hospitalisation

UB (0.008)¥5,897,299

12.5698¥4,521,816

12.3400¥1,375,483

0.2298¥5,984,553-1.54%

Use per migraine
day - A&E visit

LB (0.000)¥5,496,052

12.5698¥4,098,861

12.3400¥1,397,190

0.2298¥6,078,999

0.02%

UB (0.001)¥5,505,942

12.5698¥4,109,286

12.3400¥1,396,655

0.2298¥6,076,671-0.02%

LB (¥830)¥5,331,286

12.5698¥3,925,443

12.3400¥1,405,843

0.2298¥6,116,645

0.64%

UB (¥1,156)¥5,670,365

12.5698¥4,282,344

12.3400¥1,388,021

0.2298¥6,039,106-0.64%

LB (¥19)¥5,499,421

12.5698¥4,102,413

12.3400¥1,397,009

0.2298¥6,078,208

0.01%

UB (¥27)¥5,502,230

12.5698¥4,105,374

12.3400¥1,396,856

0.2298¥6,077,542-0.01%

LB (¥20)¥5,497,561

12.5698¥4,100,458

12.3400¥1,397,104

0.2298¥6,078,621

0.01%

UB (¥27)¥5,504,090

12.5698¥4,107,329

12.3400¥1,396,761

0.2298¥6,077,129-0.01%

LB (4.18%)¥5,517,638

12.5734¥4,103,894

12.3400¥1,413,744

0.2335¥6,055,069-0.38%

Cost of Triptans
Cost of paracetamol
containing products
Cost of
NSAID/Aspirin
Galcanezumab
discontinuation

UB (7.02%)¥5,482,202

12.5658¥4,103,894

12.3400¥1,378,308

0.2258¥6,103,994

0.43%

LB (-0.0125)¥5,500,826

12.5595¥4,103,894

12.3368¥1,396,932

0.2227¥6,271,377

3.18%

UB (-0.0111)¥5,500,826

12.5801¥4,103,894

12.3431¥1,396,932

0.2369¥5,895,956-2.99%

Utility analysis Intercept Fail 1 or 2

LB (0.7578)¥5,500,826

12.5401¥4,103,894

12.3327¥1,396,932

0.2074¥6,734,257

10.80%UB (0.7814)¥5,500,826

12.5994¥4,103,894

12.3472¥1,396,932

0.2522¥5,538,083-8.88%

Utility analysis Treatment effect Fail 1 or 2

LB (0.0125)¥5,500,826

12.5336¥4,103,894

12.3311¥1,396,932

0.2025¥6,898,932

13.51%UB (0.0412)¥5,500,826

12.6060¥4,103,894

12.3488¥1,396,932

0.2572¥5,431,464-10.64%

Utility analysis MHD Coefficient Fail 1 or 2

122

Chronic Migraine population with a history of treatment failure to 1 or
2 prior preventive migraine treatments (Propranolol comparison)
The result of the DSA in the chronic migraine patient population with a history of 1 or
2 prior preventive treatments (ie. 2nd or 3rd line preventive treatment) comparing
galcanezumab to propranolol is presented in 図 5-2 and 表 5-2. The most impactfulparameters are the mean change from baseline in monthly migraine headache days
for galcanezumab and discount rates for QALYs and costs. All upper and lower bound
ICERs remain well below the ¥5,000,000 willingness to pay threshold. 表 5-2 provides
a comprehensive overview of the results of various variables tested in thedeterministic sensitivity analysis in the chronic migraine patient population with ahistory of 1 or 2 prior preventive treatments comparing galcanezumab to propranolol.
•

図 5-2 DSA in the chronic migraine patient population with a history of 1 or 2 priorpreventive treatments (Propranolol comparison)123表 5-2 Detailed results of the DSA f or the chronic migraine patient population with a history of 1 or 2 prior preventive treatments(Propranolol comparison)
Parameter

Range

Discount rate - Cost
Baseline - Age
Baseline - Gender
Baseline - MHD
GMB response rate(30%)

Propranolol

QALY

Cost

¥9,879,533

9.3985¥9,879,533

11.6685

UB (4.00%)¥9,879,533

LB (0.00%)¥12,141,675

UB (4.00%)

Incremental

ICER

Δ ICER
in %

QALY

Cost

QALY

¥8,508,388

8.8891¥1,371,145

0.5094¥2,691,706¥8,508,388

11.1007¥1,371,145

0.5678¥2,415,000-10.28%7.7530¥8,508,388

7.2912¥1,371,145

0.4618¥2,969,262

10.31%

9.3985¥10,656,304

8.8891¥1,485,371

0.5094¥2,915,943

8.33%¥8,234,535

9.3985¥6,956,740

8.8891¥1,277,795

0.5094¥2,508,449-6.81%

LB (41.25)¥9,895,123

9.4142¥8,523,306

8.9044¥1,371,817

0.5097¥2,691,220-0.02%

Base caseDiscount rate QALY

Galcanezumab

LB (0.00%)

Cost

UB (43.37)¥9,862,446

9.3813¥8,492,049

8.8722¥1,370,397

0.5090¥2,692,247

0.02%

LB (84.74%)¥9,874,559

9.3934¥8,503,595

8.8841¥1,370,964

0.5093¥2,691,837

0.00%

UB (90.84%)¥9,884,072

9.4031¥8,512,761

8.8936¥1,371,311

0.5095¥2,691,586

0.00%

LB (19.01)¥9,710,586

9.5258¥8,339,877

9.0213¥1,370,710

0.5045¥2,716,793

0.93%-0.91%UB (19.79)¥10,048,305

9.2711¥8,676,724

8.7568¥1,371,582

0.5143¥2,667,093

LB (44.45%)¥9,662,508

9.2948¥8,508,388

8.8891¥1,154,121

0.4058¥2,844,301

5.67%

UB (64.78%)¥10,092,992

9.5004¥8,508,388

8.8891¥1,584,604

0.6113¥2,592,085-3.70%

Propranolol
response rate(30%)

LB (56.55%)¥9,879,533

9.3985¥8,509,427

8.8853¥1,370,106

0.5132¥2,669,936-0.81%UB (76.24%)¥9,879,533

9.3985¥8,507,412

8.8926¥1,372,121

0.5059¥2,712,423

0.77%

GMB - mean MHD
change

LB (-7.56)¥9,803,495

9.4428¥8,508,388

8.8891¥1,295,107

0.5537¥2,338,857-13.11%

UB (-5.56)¥9,955,401

9.3541¥8,508,388

8.8891¥1,447,013

0.4651¥3,111,469

15.59%

LB (-6.10)¥9,879,533

9.3985¥8,493,942

8.8967¥1,385,591

0.5017¥2,761,644

2.60%

UB (-3.34)¥9,879,533

9.3985¥8,522,782

8.8814¥1,356,751

0.5171¥2,623,941-2.52%

LB (¥10)¥9,879,533

9.3985¥8,507,310

8.8891¥1,372,223

0.5094¥2,693,822

0.08%

UB (¥14)¥9,879,533

9.3985¥8,509,466

8.8891¥1,370,068

0.5094¥2,689,589-0.08%

LB (¥2,634)¥9,725,842

9.3985¥8,346,435

8.8891¥1,379,407

0.5094¥2,707,924

0.60%-0.65%

Propranolol - mean
MHD change
Propranolol costs
Costs for physician
visitsCost forhospitalisation
Cost for A&E visit
Use per migraine
day - physician
visitsUse per migraine

UB (¥3,662)¥10,044,235

9.3985¥8,681,944

8.8891¥1,362,292

0.5094¥2,674,325

LB (¥143,724)¥9,084,385

9.3985¥7,670,497

8.8891¥1,413,889

0.5094¥2,775,615

3.12%

UB (¥199,851)¥10,731,653

9.3985¥9,406,313

8.8891¥1,325,340

0.5094¥2,601,784-3.34%

LB (¥28,746)¥9,869,273

9.3985¥8,497,576

8.8891¥1,371,697

0.5094¥2,692,788

0.04%

UB (¥39,972)¥9,890,529

9.3985¥8,519,974

8.8891¥1,370,554

0.5094¥2,690,545-0.04%

LB (0.060)¥9,725,842

9.3985¥8,346,435

8.8891¥1,379,407

0.5094¥2,707,924

0.60%

UB (0.083)¥10,044,235

9.3985¥8,681,944

8.8891¥1,362,292

0.5094¥2,674,325-0.65%

LB (0.006)¥9,084,385

9.3985¥7,670,497

8.8891¥1,413,889

0.5094¥2,775,615

3.12%

124

day - hospitalisation

UB (0.008)¥10,731,653

9.3985¥9,406,313

8.8891¥1,325,340

0.5094¥2,601,784-3.34%

Use per migraine
day - A&E visit

LB (0.000)¥9,869,273

9.3985¥8,497,576

8.8891¥1,371,697

0.5094¥2,692,788

0.04%

UB (0.001)¥9,890,529

9.3985¥8,519,974

8.8891¥1,370,554

0.5094¥2,690,545-0.04%

LB (¥830)¥9,557,873

9.3985¥8,170,717

8.8891¥1,387,156

0.5094¥2,723,136

1.17%

UB (¥1,156)¥10,201,193

9.3985¥8,846,058

8.8891¥1,355,135

0.5094¥2,660,275-1.17%

LB (¥19)¥9,876,419

9.3985¥8,505,104

8.8891¥1,371,316

0.5094¥2,692,040

0.01%

UB (¥27)¥9,882,647

9.3985¥8,511,672

8.8891¥1,370,975

0.5094¥2,691,371-0.01%

LB (¥20)¥9,873,342

9.3985¥8,501,888

8.8891¥1,371,454

0.5094¥2,692,311

0.02%

UB (¥27)¥9,885,724

9.3985¥8,514,887

8.8891¥1,370,837

0.5094¥2,691,100-0.02%

LB (3.81%)¥9,901,819

9.4091¥8,508,388

8.8891¥1,393,431

0.5200¥2,679,460-0.45%

Cost of Triptans
Cost of paracetamol
containing products
Cost of
NSAID/Aspirin
Galcanezumab
discontinuation
Utility analysis MHD Coefficient –Fail 1 or 2
Utility analysis Intercept – Fail 1 or
2
Utility analysis Treatment effect –Fail 1 or 2

UB (7.72%)¥9,853,929

9.3862¥8,508,388

8.8891¥1,345,542

0.4972¥2,706,418

0.55%

LB (-0.0125)¥9,879,533

9.3716¥8,508,388

8.8819¥1,371,145

0.4897¥2,799,714

4.01%

UB (-0.0111)¥9,879,533

9.4253¥8,508,388

8.8963¥1,371,145

0.5290¥2,591,721-3.71%

LB (0.7578)¥9,879,533

9.3650¥8,508,388

8.8816¥1,371,145

0.4834¥2,836,563

5.38%

UB (0.7814)¥9,879,533

9.4319¥8,508,388

8.8965¥1,371,145

0.5354¥2,560,924-4.86%

LB (0.0125)¥9,879,533

9.3576¥8,508,388

8.8800¥1,371,145

0.4776¥2,870,710

6.65%

UB (0.0412)¥9,879,533

9.4393¥8,508,388

8.8982¥1,371,145

0.5412¥2,533,715-5.87%

125

Episodic Migraine population with a history of treatment failure to atleast 3 prior preventive migraine treatments (BSC comparison)
The result of the DSA in the episodic migraine patient population with a history of 3
or more prior preventive treatments (ie. at least 4th line preventive treatment)
comparing galcanezumab to BSC is presented in 図 5-3 and 表 5-3. The most impactfulparameters are the utility treatment effect and utility intercept estimated based on
the clinical trial program of galcanezumab for the patient population who had atreatment history of 3 or more prior preventive treatments followed by the meanchange from baseline in monthly migraine headache days for galcanezumab patients
who achieved at least a 50% response rate. All upper and lower bound ICERs remain
well below the ¥5,000,000 willingness to pay threshold. 表 5-3 provides acomprehensive overview of the results of various variables tested in the deterministic
sensitivity analysis in the episodic migraine patient population with a history of 3 ormore prior preventive treatments comparing galcanezumab to BSC.
•

図 5-3 DSA in the episodic migraine patient population with a history of 3 or moreprior preventive treatments (BSC comparison)126

表 5-3 Detailed results of the DSA f or the episodic migraine patient population with a history of 3 or more prior preventive
treatments (BSC comparison)
Parameter

Range

Base caseDiscount rate QALY
Discount rate - Cost
Baseline - Age
Baseline - Gender
Baseline - MHD
GMB response rate
(50%)
BSC response rate
(50%)
GMB responders mean MHD change

Galcanezumab

BSC

Incremental

Cost

QALY

Cost

QALY

Cost

QALY

ICER

Δ ICR in %¥5,539,801

12.1581¥4,452,735

11.7767¥1,087,066

0.3814¥2,850,240

LB (0.00%)¥5,539,801

15.1408¥4,452,735

14.7210¥1,087,066

0.4198¥2,589,673-9.14%UB (4.00%)¥5,539,801

9.9978¥4,452,735

9.6478¥1,087,066

0.3500¥3,105,702

8.96%

LB (0.00%)¥6,743,737

12.1581¥5,571,914

11.7767¥1,171,824

0.3814¥3,072,472

7.80%

UB (4.00%)¥4,661,289

12.1581¥3,643,512

11.7767¥1,017,777

0.3814¥2,668,569-6.37%

LB (45.09)¥5,552,711

12.1904¥4,464,858

11.8086¥1,087,853

0.3817¥2,849,672-0.02%UB (47.43)¥5,525,718

12.1229¥4,439,496

11.7419¥1,086,223

0.3810¥2,850,848

0.02%

LB (82.01%)¥5,534,431

12.1446¥4,447,641

11.7633¥1,086,789

0.3813¥2,850,440

0.01%

UB (90.00%)¥5,544,653

12.1703¥4,457,338

11.7888¥1,087,315

0.3815¥2,850,059-0.01%

LB (9.37)¥5,402,710

12.2517¥4,315,802

11.8728¥1,086,907

0.3789¥2,868,780

0.65%-0.64%UB (9.97)¥5,676,784

12.0646¥4,589,574

11.6806¥1,087,211

0.3839¥2,831,910

LB (31.50%)¥5,316,325

12.0603¥4,452,735

11.7767¥863,590

0.2836¥3,045,334

6.84%

UB (54.31%)¥5,769,916

12.2588¥4,452,735

11.7767¥1,317,180

0.4821¥2,732,078-4.15%

LB (3.60%)¥5,539,801

12.1581¥4,467,258

11.7673¥1,072,543

0.3908¥2,744,521-3.71%UB (31.36%)¥5,539,801

12.1581¥4,431,760

11.7903¥1,108,041

0.3678¥3,012,471

5.69%

LB (-7.98)¥5,497,480

12.1807¥4,452,735

11.7767¥1,044,745

0.4040¥2,585,922-9.27%UB (-6.44)¥5,581,965

12.1355¥4,452,735

11.7767¥1,129,230

0.3588¥3,147,414

10.43%

GMB nonresponders - mean
MHD change

LB (-1.90)¥5,534,185

12.1621¥4,452,735

11.7767¥1,081,450

0.3853¥2,806,484-1.54%UB (-0.52)¥5,545,409

12.1542¥4,452,735

11.7767¥1,092,674

0.3774¥2,894,890

1.57%

BSC responders mean MHD change

LB (-8.51)¥5,539,801

12.1581¥4,449,296

11.7785¥1,090,505

0.3796¥2,872,685

0.79%

UB (-5.91)¥5,539,801

12.1581¥4,456,151

11.7749¥1,083,650

0.3832¥2,828,076-0.78%

BSC non-responders- mean MHD change

LB (-0.02)¥5,539,801

12.1581¥4,451,756

11.7774¥1,088,045

0.3807¥2,857,9780.27%

UB (1.16)¥5,539,801

12.1581¥4,453,713

11.7760¥1,086,088

0.3821¥2,842,534-0.27%

Costs for physician
visits

LB (¥2,634)¥5,466,535

12.1581¥4,372,528

11.7767¥1,094,007

0.3814¥2,868,440

0.64%

UB (¥3,662)¥5,618,316

12.1581¥4,538,689

11.7767¥1,079,627

0.3814¥2,830,736-0.68%

LB (¥143,724)¥5,160,746

12.1581¥4,037,769

11.7767¥1,122,977

0.3814¥2,944,399

3.30%

UB (¥199,851)¥5,946,014

12.1581¥4,897,434

11.7767¥1,048,581

0.3814¥2,749,334-3.54%

LB (¥28,746)¥5,534,910

12.1581¥4,447,381

11.7767¥1,087,529

0.3814¥2,851,455

0.04%

UB (¥39,972)¥5,545,042

12.1581¥4,458,474

11.7767¥1,086,569

0.3814¥2,848,938-0.05%

LB (0.060)¥5,466,535

12.1581¥4,372,528

11.7767¥1,094,007

0.3814¥2,868,440

0.64%

Cost forhospitalisation
Cost for A&E visit
Use per migraine127

day - physician
visitsUB (0.083)¥5,618,316

12.1581¥4,538,689

11.7767¥1,079,627

0.3814¥2,830,736-0.68%

Use per migraine
day - hospitalisation

LB (0.006)¥5,160,746

12.1581¥4,037,769

11.7767¥1,122,977

0.3814¥2,944,399

3.30%

UB (0.008)¥5,946,014

12.1581¥4,897,434

11.7767¥1,048,581

0.3814¥2,749,334-3.54%

Use per migraine
day - A&E visit

LB (0.000)¥5,534,910

12.1581¥4,447,381

11.7767¥1,087,529

0.3814¥2,851,455

0.04%

UB (0.001)¥5,545,042

12.1581¥4,458,474

11.7767¥1,086,569

0.3814¥2,848,938-0.05%

Average cost of
Triptans

LB (¥830)¥5,348,610

12.1581¥4,243,618

11.7767¥1,104,992

0.3814¥2,897,244

1.65%

UB (¥1,156)¥5,730,991

12.1581¥4,661,853

11.7767¥1,069,139

0.3814¥2,803,236-1.65%

Average cost ofparacetamol
containing products

LB (¥19)¥5,538,992

12.1581¥4,451,842

11.7767¥1,087,150

0.3814¥2,850,461

0.01%

UB (¥27)¥5,540,610

12.1581¥4,453,629

11.7767¥1,086,981

0.3814¥2,850,019-0.01%

Average cost of
NSAID/Aspirin

LB (¥20)¥5,536,777

12.1581¥4,449,414

11.7767¥1,087,362

0.3814¥2,851,018

0.03%

UB (¥27)¥5,542,825

12.1581¥4,456,056

11.7767¥1,086,769

0.3814¥2,849,462-0.03%

LB (4.18%)¥5,551,924

12.1634¥4,452,735

11.7767¥1,099,189

0.3867¥2,842,470-0.27%

Galcanezumab
discontinuation
Utility analysis MHD Coefficient –Fail 3 or more
Utility analysis Intercept – Fail 3 ormore
Utility analysis Treatment effect –Fail 3 or more

UB (7.02%)¥5,526,371

12.1522¥4,452,735

11.7767¥1,073,636

0.3755¥2,859,102

0.31%

LB (-0.0134)¥5,539,801

12.1515¥4,452,735

11.7749¥1,087,066

0.3766¥2,886,526

1.27%

UB (-0.0114)¥5,539,801

12.1647¥4,452,735

11.7785¥1,087,066

0.3862¥2,814,855-1.24%

LB (0.7292)¥5,539,801

12.1150¥4,452,735

11.7715¥1,087,066

0.3435¥3,164,331

11.02%UB (0.7674)¥5,539,801

12.2012¥4,452,735

11.7820¥1,087,066

0.4193¥2,592,872-9.03%

LB (0.0376)¥5,539,801

12.1126¥4,452,735

11.7767¥1,087,066

0.3359¥3,236,131

13.54%UB (0.0779)¥5,539,801

12.2036¥4,452,735

11.7767¥1,087,066

0.4269¥2,546,575-10.65%128

Chronic Migraine population with a history of treatment failure to atleast 3 prior preventive migraine treatments (BSC comparison)
The result of the DSA in the chronic migraine patient population with a history of 3 ormore prior preventive treatments (ie. at least 4th line preventive treatment) comparing
galcanezumab to BSC is presented in 図 5-4 and 表 5-4. The most impactfulparameters are the mean change from baseline in monthly migraine headache daysin patients treated with galcanezumab who achieved a 30% response rate, followedby discount rate for QALYs and the utility treatment effect of galcanezumab over BSC.
All upper and lower bound ICERs remain well below the ¥5,000,000 willingness to pay
threshold. 表 5-4 provides a comprehensive overview of the results of various
variables tested in the deterministic sensitivity analysis in the hronic migraine patient
population with a history of 3 or more prior preventive treatments comparing
galcanezumab to BSC.
•

図 5-4 DSA results f or the chronic migraine patient population with a history of 3 ormore prior preventive treatments (BSC comparison)129表 5-4 Detailed results of the DSA f or the chronic migraine patient population with a history of 3 or more prior preventive
treatments (BSC comparison)
Parameter

Range

Discount rate - Cost
Baseline - Age
Baseline - Gender
Baseline - MHD
GMB response rate
(30%)
BSC response rate(30%)
GMB responders mean MHD change

BSC

QALY

Cost

¥9,853,551

9.4390¥9,853,551

11.6873

UB (4.00%)¥9,853,551

LB (0.00%)¥12,144,665

UB (4.00%)

Incremental

ICER

Δ ICER
in %

QALY

Cost

QALY

¥8,793,870

8.7040¥1,059,682

0.7350¥1,441,739¥8,793,870

10.8756¥1,059,682

0.8117¥1,305,479-9.45%

7.8063¥8,793,870

7.1340¥1,059,682

0.6723¥1,576,214

9.33%

9.4390¥11,005,834

8.7040¥1,138,830

0.7350¥1,549,423

7.47%¥8,189,754

9.4390¥7,194,770

8.7040¥994,984

0.7350¥1,353,714-6.11%

LB (44.31)¥9,877,182

9.4622¥8,816,789

8.7265¥1,060,393

0.7357¥1,441,382-0.02%
0.03%

Base caseDiscount rate QALY

Galcanezumab
Cost

LB (0.00%)

UB (46.67)¥9,827,887

9.4138¥8,768,963

8.6795¥1,058,923

0.7343¥1,442,120

LB (81.46%)¥9,844,517

9.4301¥8,785,061

8.6953¥1,059,455

0.7348¥1,441,854

0.01%

UB (89.09%)¥9,861,803

9.4471¥8,801,915

8.7119¥1,059,889

0.7352¥1,441,634-0.01%

LB (18.80)¥9,636,568

9.5878¥8,577,220

8.8579¥1,059,349

0.7299¥1,451,419

0.67%-0.66%UB (19.76)¥10,070,437

9.2901¥9,010,422

8.5500¥1,060,016

0.7401¥1,432,194

LB (43.37%)¥9,689,114

9.2829¥8,793,870

8.7040¥895,244

0.5789¥1,546,385

7.26%

UB (65.89%)¥10,014,961

9.5922¥8,793,870

8.7040¥1,221,091

0.8882¥1,374,787-4.64%

LB (11.31%)¥9,853,551

9.4390¥8,810,593

8.6903¥1,042,958

0.7486¥1,393,146-3.37%UB (33.77%)¥9,853,551

9.4390¥8,774,114

8.7201¥1,079,437

0.7189¥1,501,514

4.15%

LB (-12.40)¥9,790,969

9.4729¥8,793,870

8.7040¥997,1000.7689¥1,296,810-10.05%

UB (-10.59)¥9,916,086

9.4051¥8,793,870

8.7040¥1,122,217

0.7011¥1,600,609

11.02%

GMB nonresponders - mean
MHD change

LB (-1.12)¥9,847,042

9.4436¥8,793,870

8.7040¥1,053,172

0.7396¥1,423,884-1.24%UB (0.88)¥9,860,057

9.4343¥8,793,870

8.7040¥1,066,187

0.7304¥1,459,815

1.25%

BSC responders mean MHD change

LB (-10.31)¥9,853,551

9.4390¥8,789,969

8.7060¥1,063,583

0.7329¥1,451,102

0.65%

UB (-8.23)¥9,853,551

9.4390¥8,797,767

8.7019¥1,055,785

0.7371¥1,432,433-0.65%

BSC non-responders- mean MHD change

LB (0.33)¥9,853,551

9.4390¥8,793,053

8.7046¥1,060,498

0.7344¥1,443,995

0.16%-0.16%

Costs for physician
visitsCost forhospitalisation
Cost for A&E visit
Use per migraine

UB (1.41)¥9,853,551

9.4390¥8,794,685

8.7034¥1,058,866

0.7356¥1,439,487

LB (¥2,634)¥9,707,193

9.4390¥8,633,646

8.7040¥1,073,548

0.7350¥1,460,604

1.31%

UB (¥3,662)¥10,010,396

9.4390¥8,965,573

8.7040¥1,044,823

0.7350¥1,421,522-1.40%

LB (¥143,724)¥9,096,340

9.4390¥7,964,921

8.7040¥1,131,419

0.7350¥1,539,340

6.77%

UB (¥199,851)¥10,665,016

9.4390¥9,682,211

8.7040¥982,805

0.7350¥1,337,145-7.25%

LB (¥28,746)¥9,843,780

9.4390¥8,783,173

8.7040¥1,060,607

0.7350¥1,442,998

0.09%

UB (¥39,972)¥9,864,022

9.4390¥8,805,333

8.7040¥1,058,690

0.7350¥1,440,389-0.09%

LB (0.060)¥9,707,193

9.4390¥8,633,646

8.7040¥1,073,548

0.7350¥1,460,604

1.31%

130

day - physician
visitsUB (0.083)¥10,010,396

9.4390¥8,965,573

8.7040¥1,044,823

0.7350¥1,421,522-1.40%

Use per migraine
day - hospitalisation

LB (0.006)¥9,096,340

9.4390¥7,964,921

8.7040¥1,131,419

0.7350¥1,539,340

6.77%

UB (0.008)¥10,665,016

9.4390¥9,682,211

8.7040¥982,805

0.7350¥1,337,145-7.25%

Use per migraine
day - A&E visit

LB (0.000)¥9,843,780

9.4390¥8,783,173

8.7040¥1,060,607

0.7350¥1,442,998

0.09%

UB (0.001)¥9,864,022

9.4390¥8,805,333

8.7040¥1,058,690

0.7350¥1,440,389-0.09%

Average cost of
Triptans

LB (¥830)¥9,488,370

9.4390¥8,394,690

8.7040¥1,093,680

0.7350¥1,487,995

3.21%

UB (¥1,156)¥10,218,732

9.4390¥9,193,049

8.7040¥1,025,684

0.7350¥1,395,483-3.21%

Average cost ofparacetamol
containing products

LB (¥19)¥9,851,083

9.4390¥8,791,136

8.7040¥1,059,947

0.7350¥1,442,100

0.03%

UB (¥27)¥9,856,020

9.4390¥8,796,603

8.7040¥1,059,416

0.7350¥1,441,378-0.03%

Average cost of
NSAID/Aspirin

LB (¥20)¥9,846,615

9.4390¥8,786,244

8.7040¥1,060,371

0.7350¥1,442,677

0.07%

UB (¥27)¥9,860,487

9.4390¥8,801,495

8.7040¥1,058,992

0.7350¥1,440,801-0.07%

LB (3.81%)¥9,868,794

9.4534¥8,793,870

8.7040¥1,074,924

0.7495¥1,434,240-0.52%

Galcanezumab
discontinuation
Utility analysis MHD Coefficient Fail 3 or more
Utility analysis –Intercept - Fail 3 ormore
Utility analysis Treatment effect Fail 3 or more

UB (7.72%)¥9,836,040

9.4224¥8,793,870

8.7040¥1,042,171

0.7184¥1,450,726

0.62%

LB (-0.0134)¥9,853,551

9.4153¥8,793,870

8.6993¥1,059,682

0.7161¥1,479,892

2.65%

UB (-0.0114)¥9,853,551

9.4626¥8,793,870

8.7087¥1,059,682

0.7540¥1,405,504-2.51%

LB (0.7292)¥9,853,551

9.3847¥8,793,870

8.6978¥1,059,682

0.6869¥1,542,736

7.01%

UB (0.7674)¥9,853,551

9.4933¥8,793,870

8.7102¥1,059,682

0.7831¥1,353,153-6.14%

LB (0.0376)¥9,853,551

9.3817¥8,793,870

8.7040¥1,059,682

0.6777¥1,563,629

8.45%

UB (0.0779)¥9,853,551

9.4963¥8,793,870

8.7040¥1,059,682

0.7923¥1,337,478-7.23%

131

5.1.2.3 Probabilistic sensitivity analyses
基本分析に関する確率的感度分析の概要と結果を以下に述べる。
A probabilistic sensitivity analysis (PSA) was conducted by assigning distributions
to all input parameters and randomly sampling f rom these distributions over
1,000 Monte Carlo simulations to calculate the uncertainty in costs and outcomes.
A summary of the distributions chosen f or the probabilistic parameters in themodel is provided in 表 5-5.
表 5-5 Model parameter summary
Parameter

Distribution

Age

Normal distribution

Gender

Beta distribution

Baseline Migraine
Headache Days

Normal distribution

Distribution parameters

Variance covariancematrixMean change in
Migraine Headache
Days

Normal distribution

Response rate

Beta distribution

Drug costs

Normal distribution

Resource costs

Gamma distribution

Resource use

Gamma distribution

Discontinuation

Beta distribution

Utility values

Normal distribution

Justification
Based on theinformation
available from thetrial data
Based on naturallimit between 0 and100%.
Based on theinformation
available from thetrial data
Used to account for
uncertainty inregression
parameters
Aligned with
galcanezumab trial
programBased on naturallimit between 0 and
100%.
Assumption of
uncertainty aroundthe mean
Based on an
anticipated skewed
distribution
Based on theinformation
available from thetrial data
Based on naturallimit between 0 and
100%.
Variance takenfrom trial analysis

Description
Section 4.2.1

Section 4.2.1

Section 4.2.1

Section 4.2.1

Section 4.2.1
Section 4.2.1
Section 4.2.3
Section 4.2.3

Section 4.2.3

Section 4.2.1
Section 4.2.2

Episodic Migraine population with a history of treatment failure to
1 or 2 prior preventive migraine treatments (Propranolol
comparison)
表 5-6, 図 5-5 and 図 5-6 show the f indings f rom the PSA f or the episodic migraine
patient population with a history of 1 or 2 prior preventive treatments (ie. 2nd or
3rd line preventive treatments) comparing to propranolol. The mean ICER
derived f rom the PSA run with 1,000 iterations (表 5-6) is marginally lower•

compared to the deterministic base case analysis (¥5,839,366 compared to¥6,077,875).
表 5-6 Probabilistic results f or the episodic migraine patient population f ailed 1
or 2 prior preventive migraine treatments (Propranolol comparison)
Treatment

QALY

Δ QALY

Cost (yen)Δ Cost(yen)

ICER(yen/QALY)

Galcanezuma
b 120mg15.6870.258¥6,641,876¥1,506,531¥5,839,366

Propranolol

15.429/¥5,135,345//

図 5-5 shows the cost-ef fectives plane f rom the PSA, and theref ore the level of
uncertainty surrounding model parameters. The f indings f or the episodic
migraine patient population with a history of 1 or 2 prior preventive treatments(ie. 2nd or 3rd line preventive treatments) comparing to propranolol show that
all iterations f all within the north-east quadrant f or the cost-ef fectives plane. Thisf inding suggests that galcanezumab will result in both incremental costs and
QALY gains compared to propranolol. The three lines of treatment ref lect thewillingness to pay thresholds of ¥5,000,000 (grey line), ¥7,500,000 (blue line)and ¥10,000,000 (red line) and the blue dots ref lect each individual draw. The
red dot represents the average ICER across the 1,000 iterations. All iterations
are below the WTP threshold of ¥7,500,000 (blue line).
図 5-5 Scatterplot f or the episodic migraine patient population f ailed 1 or 2 priorpreventive migraine treatments (Propranolol comparison)

図 5-6 shows the probability of galcanezumab being cost-ef f ectiveness at various
WTP thresholds. In general, when the willingness to pay (WTP) thresholdincreases, so does the probability of cost-ef fectiveness f or galcanezumab. The
dotted lines represent the willingness to pay thresholds of ¥5,000,000;
133

¥7,500,000 and ¥10,000,000. Galcanezumab has a probability of being costef f ective compared to propranolol in the episodic migraine patient population witha history of 1 or 2 prior migraine treatments of 9.5% at a WTP threshold of¥5,000,000; 96.0% at ¥7,500,000 and 99.9% at ¥10,000,000.
図 5-6 Cost ef f ectiveness acceptability curve (CEAC) f or the episodic migraine
patient population f ailed 1 or 2 prior preventive migraine treatments(Propranolol comparison)

Chronic Migraine population with a history of treatment failure to
1 or 2 prior preventive migraine treatments (Propranolol
comparison)
表 5-7, 図 5-7 and 図 5-8 show the f indings f rom the PSA f or the chronic migraine
patient population with a history of 1 or 2 prior preventive treatments (ie. 2nd or
3rd line preventive treatments) comparing to propranolol. The mean ICER
derived f rom the PSA run with 1,000 iterations (表 5-7) is comparable to thedeterministic base case analysis (¥2,601,300 compared to ¥2,691,706).
•

表 5-7 Probabilistic results f or the chronic migraine patient population f ailed 1 or
2 prior preventive migraine treatments (Propranolol comparison)
Treatment

QALY

Δ QALY

Galcanezuma
b 120mg11.6650.566

Propranolol

11.099/

Cost (yen)¥12,167,64
0¥10,694,65
8

Δ Cost(yen)

ICER(yen/QALY)¥1,472,982¥2,601,300//

The f indings of the cost-ef f ectiveness plane f or the episodic migraine patient
population with a history of 1 or 2 prior preventive treatments (ie. 2nd or 3rdline preventive treatments) comparing to propranolol show that all iterations f all
within the north-east quadrant. This suggests that galcanezumab will result inboth incremental costs and QALY gains compared to propranolol (図 5-7). All
1,000 iterations are below the ¥5,000,000 WTP threshold.
134図 5-7 PSA scatterplot f or the chronic migraine patient population f ailed 1 or 2prior preventive migraine treatments (Propranolol comparison)

Galcanezumab has a 100% probability of being cost-ef fective compared topropranolol in the chronic migraine patient population with a history of 1 priormigraine treatment at all three WTP thresholds (図 5-8).
図 5-8 CEAC f or the chronic migraine patient population f ailed 1 or 2 priorpreventive migraine treatments (Propranolol comparison)

Episodic Migraine population with a history of treatment failure toat least 3 prior preventive migraine treatments (BSC comparison)
表 5-8, 図 5-9 and 図 5-10 show the f indings f rom the PSA f or the episodic
migraine population with a history of 3 or more prior preventive treatments (ie.
135•

at least 4th line preventive migraine treatment) comparing to BSC. The mean
ICER derived f rom the PSA run with 1,000 iterations (表 5-8) is marginally lower
compared to the deterministic base case analysis (¥2,786,587 compared to¥2,850,240).
表 5-8 Probabilistic results f or the episodic migraine patient population f ailed 3
or more prior preventive migraine treatments (BSC comparison)
Treatment

QALY

Δ QALY

Cost (yen)Δ Cost(yen)

ICER(yen/QALY)

Galcanezuma
b 120mg15.142

0.422¥6,735,933¥1,175,460¥2,786,587

BSC

14.720/¥5,560,473//

The f indings f rom the PSA scatterplot f or the episodic migraine patient population
with a history of 3 or more prior preventive treatments (ie. at least 4th line
preventive treatment) comparing to BSC show that all iterations f all within thenorth-east quadrant f or the cost-ef f ectives plane. This suggests that
galcanezumab will result in both incremental costs and QALY gains compared to
BSC (図 5-9).
図 5-9 PSA scatterplot f or the episodic migraine patient population f ailed 3 ormore prior preventive migraine treatments (BSC comparison)

Galcanezumab has a 100.0% probability of being cost-ef f ective compared to BSC
in the episodic migraine patient population with a history of 3 or more priormigraine treatments at all WTP thresholds (図 5-10).

136

図 5-10 CEAC f or the episodic migraine patient population f ailed 3 or more priorpreventive migraine treatments (BSC comparison)

Chronic Migraine population with a history of treatment failure toat least 3 prior preventive migraine treatments (BSC comparison)
表 5-9, 図 5-11 and 図 5-12 show the f indings f rom the PSA f or the chronic
migraine population with a history of 3 or more prior preventive treatments (ie.
at least 4th line preventive migraine treatment) comparing to BSC. The mean
ICER derived f rom the PSA run with 1,000 iterations (表 5-9) is comparable tothe deterministic base case analysis (¥1,400,388 compared to ¥1,441,739).
•

表 5-9 Probabilistic results f or the chronic migraine patient population f ailed 3 ormore prior preventive migraine treatments (BSC comparison)
Treatment

QALY

Δ QALY

Galcanezuma
b 120mg11.6890.811

BSC

10.878/

Cost (yen)¥12,118,74
3¥10,982,44
3

Δ Cost(yen)

ICER(yen/QALY)¥1,136,299¥1,400,388//

The f indings f rom the PSA scatterplot f or the chronic migraine patient population
with a history of 3 or more prior preventive treatments (ie. line preventive
treatment) comparing to BSC show that all iterations f all within the north-east
quadrant f or the cost-ef f ectives plane. This suggests that galcanezumab will
result in both incremental costs and QALY gains compared to BSC (図 5-11).

137

図 5-11 PSA scatterplot f or the chronic migraine patient population f ailed 3 ormore prior preventive migraine treatment (BSC comparison)

Galcanezumab has a 100% probability of being cost-ef fective compared to BSC
in the chronic migraine patient population with a history of 3 or more priormigraine treatments at all WTP thresholds (図 5-12).
図 5-12 CEAC f or the chronic migraine patient population f ailed 3 or more priorpreventive migraine treatment (BSC comparison)1385.1.2.4 Scenario analysis
1.Episodic Migraine population with a history of treatment failure to 1 or
2 prior preventive migraine treatments (Propranolol comparison)
表 5-10 shows the ICERs derived from the scenario analyses for the episodic
migraine population with a history of treatment failure to 1 or 2 prior preventive
migraine treatments (ie. 2nd or 3rd line preventive treatment) comparing
galcanezumab to Propranolol. A shorter time horizon and assuming that patientson galcanezumab loose return to baseline already 5 months after stopping
treatment appeared to have the most significant impact on the ICER. Apart fromthese analyses, all others were in the range of the base case or even below thebase case results. All ICERs remained below the WTP threshold of ¥7,500,000.
表 5-10 Scenario analyses in the episodic migraine population with a history oftreatment f ailure to 1 or 2 prior preventive migraine treatments (Propranolol
comparison)
Scenario

Scenario Details

ICER

Δ (¥)

¥6,077,87

Base Case

5

Discount rates (costs,

0%¥5,907,622-2.80%

benef its)

4%

¥6,248,243

2.80%

5 years¥7,469,101

10 Years¥6,410,513

5.47%

45 Years¥6,063,498-0.24%

Beta-Binomial¥6,079,175

0.02%Upper level: 1.25

¥6,269,869

3.16%

Lower level: 0.75

¥5,896,856-2.98%¥6,679,060

9.89%¥6,318,895

3.97%

Time horizon

22.89
%

Distribution around
Migraine Headache Days,EM
Persistency rate

5cyclesf orbothresponders

and

non-

Treatment waning,

responders

galcanezumab

13 cycles f or responders
and

1

cycle

f or

non-

responders

2.Chronic Migraine population with a history of treatment failure to 1 or139

2 prior preventive migraine treatments (Propranolol comparison)
表 5-11 shows the ICERs derived from the scenario analyses for the chronic
migraine population with a history of treatment failure to 1 or 2 prior preventive
migraine treatments (ie. 2nd or 3rd line preventive treatment) comparing
galcanezumab to Propranolol. A shorter time horizon and considering a 50% or
greater reduction in migraine headache days appeared to have the mostsignificant negative impact on the ICER, while the treatment waning period
informed by REGAIN had the most significant positive impact on the ICER in
favour of galcanezumab. Apart from these analyses, all others were in the rangeof the base case or even below the base case results. All ICERs remained well
below the WTP threshold of ¥5,000,000.
表 5-11 Scenario analyses in the chronic migraine population with a history oftreatment f ailure to 1 or 2 prior preventive migraine treatments (Propranolol
comparison)
Scenario

Scenario Details

ICER

Δ (¥)

¥2,691,70

Base Case

6

Discount rates (costs,

0%¥2,616,185-2.81%

benef its)

4%

¥2,767,109

2.80%

5 years¥3,301,206

10 Years¥2,838,702

5.46%

45 Years¥2,685,276-0.24%

Negative-Binomial¥2,773,867

3.05%

50%

¥2,980,861

Upper level: 1.25

¥2,774,555

3.08%

Lower level: 0.75

¥2,613,060-2.92%

Time horizon

22.64
%

Distribution around
Migraine Headache Days,
EM
Response rate

10.74
%

Persistency rate

Treatment waning,galcanezumab

Return to baseline using
a
0.23

rate
MHD/cycleof¥1,694,657

37.04
%

140

3.Episodic Migraine population with a history of treatment failure to 3 ormore prior preventive migraine treatments (BSC comparison)
表 5-12 shows the ICERs derived from the scenario analyses for the episodic
migraine population with a history of treatment failure to 3 or more priorpreventive migraine treatments (ie. at least 4th line preventive treatment)
comparing galcanezumab to BSC. A shorter time horizon and assuming thatpatients on galcanezumab loose return to baseline already 5 months after
stopping treatment appeared to have the most significant impact on the ICER.
Apart from these analyses, all others were in the range of the base case or evenbelow the base case results. All ICERs remained below the WTP threshold of¥5,000,000.
表 5-12 Scenario analyses in the episodic migraine population with a history oftreatment f ailure to 3 or more prior preventive migraine treatments (BSC
comparison)
Scenario

Scenario Details

ICER

Δ (¥)

¥2,850,24

Base Case0

Discount rates (costs,

0%¥2,791,588-2.06%

benef its)

4%

¥2,907,748

2.02%

5 years¥3,259,714

10 Years¥2,956,101

3.71%

45 Years¥2,845,703-0.16%

Beta-Binomial¥2,848,415-0.06%

Due to adverse events¥2,683,789-5.84%¥3,052,558

7.10%¥2,917,590

2.36%Time horizon

14.37
%

Distribution around
Migraine Headache Days,
EM
Discontinuation,
galcanezumab

5Treatment waning,galcanezumab

cyclesf orbothresponders

and

non-

responders
13 cycles f or responders
and

1

cycle

f or

non-

responders

141

4.Chronic Migraine population with a history of treatment failure to 3 ormore prior preventive migraine treatments (BSC comparison)
表 5-13 shows the ICERs derived from the scenario analyses for the chronic
migraine population with a history of treatment failure to 3 or more priorpreventive migraine treatments (ie. at least 4th line preventive treatment)
comparing galcanezumab to BSC. A shorter time horizon appeared to have themost significant negative impact on the ICER, while the treatment waning period
informed by REGAIN, the 50% or greater reduction in monthly migraine headachedays and discontinuation due to adverse events had the most significant positive
impact on the ICER in favour of galcanezumab. Apart from these analyses, allothers were in the range of the base case results. All ICERs remained well below
the WTP threshold of ¥5,000,000.
表 5-13 Scenario analyses in the chronic migraine population with a history oftreatment f ailure to 3 or more prior preventive migraine treatments (BSC
comparison)
Scenario

Scenario Details

ICER

Δ (¥)

¥1,441,73

Base Case

9

Discount rates (costs,

0%¥1,402,986-2.69%

benef its)

4%

¥1,479,979

2.65%

5 years¥1,720,253

10 Years¥1,512,519

4.91%

45 Years¥1,438,696-0.21%

Negative-Binomial¥1,481,667

2.77%

Time horizon

19.32
%

Distribution around
Migraine Headache Days,
EM
Response rate50%

¥1,225,422

15.00
%

Discontinuation,
galcanezumab

Due to adverse events

Treatment waning,

Return to baseline using

galcanezumaba rate of 0.23 MHD/cycle¥1,340,426-7.03%-¥1,023,067

29.04
%

142

5.1.3 分析の妥当性の検討
本分析結果は、分析フレームワークに従って分析したものであるが、 プロプラノロールの長期有効性に関するエビデンスが限定的であるため、プロプラノロールの有効性とマルコフモ デ ルの外部妥当性は十分に評価されていない。JMDC のデータでは、治療期間は 24 ヶ月までであり、本分析は実臨床を適切に反映したものである。 医療資源の使用頻度についても菊井らによ る報告
50 を使用しているので、実臨床を反映していると考える。
5.1.4 分析結果の解釈
表 5-14 分析結果の解釈（ａ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う反復性片頭痛
対象集団
患者
比較対照

プロプラノロール

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 の所属する確率が最も高いと考える区 □ 750 万円超 (1125 万円超)かつ 1000 万円以下 (1500 万円以下)
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

そのように判断した理
由

プロプラノロールと比較した場合の本対象集団の ICER は、ベースケースで6,077,875 円であった。DSA によれば、検討されたすべてのシナリオでICER は 500 万円から 750 万円の間である。また、PSA の CEAC によると、ICER が 500 万円未満になる確率は 9.5％、750 万円以上になる確率
は 4.0％（100.0％ - 96.0％＝4.0％） で、いずれも低いと想定される。したがって、このグループの ICER は「500 万円以上、750 万円以下」の確率が最も高いと推測される。

対象集団（ｂ）片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う慢性片頭痛患者

比較対照

プロプラノロール

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 の所属する確率が最も高いと考える区 □ 750 万円超 (1125 万円超)かつ 1000 万円以下 (1500 万円以下)
間□ 1000 万円超 (1500 万円超)□
そのように判断した理由

効果が同等（あるいは劣り）、かつ費用が高い

プロプラノロールと比較した本対象集団の ICER は、ベースケースで2,691,706 円であった。DSA によると、ICER が 500 万円を超えるシナリ
オはない。また、PSA の CEAC では、ICER が 500 万円以下となる確率は
143

100％であることが示されている。したがって、このグループの ICER は「≦500 万円」である可能性が最も高いと推測される。

対象集団（ｃ）片頭痛予防薬の 3 剤目の治療を中止した反復性片頭痛患者

比較対照Best Supportive Care

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 の所属する確率が最も高いと考える区 □ 750 万円超 (1125 万円超)かつ 1000 万円以下 (1500 万円以下)
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

そのように判断した理由

BSC と比較した場合の 本対象集団の ICER は、ベースケースで2,850,240 円である。DSA によると、ICER が 500 万円を超えるシナリオ
はない。また、PSA の CEAC では、ICER が 500 万円以下となる確率は100％であることが示されている。したがって、このグループの ICER は「≦500 万円」である可能性が最も高いと推測される。

対象集団（ｄ）片頭痛予防薬の 3 剤目の治療を中止した慢性片頭痛患者

比較対照Best Supportive Care

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 の所属する確率が最も高いと考える区 □ 750 万円超 (1125 万円超)かつ 1000 万円以下 (1500 万円以下)
間□ 1000 万円超 (1500 万円超)□
そのように判断した理由

効果が同等（あるいは劣り）、かつ費用が高い

BSC と比較した場合の 本対象集団の ICER は、ベースケースで1,441,739 円であった。DSA によると、ICER が 500 万円を超えるシナリ
オはない。また、PSA の CEAC では、ICER が 500 万円以下となる確率は100％であることが示されている。したがって、このグループの ICER は「≦500 万円」である可能性が最も高いと推測される。

5.1.5 価格調整率の重み [該当する場合のみ]
価格調整率の重みについて以下に詳細を述べる。
5.1.5.1 片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う患者と片頭痛予防薬の 3 剤
144

目の治療を中止した患者の割合
分析対象とする集団は、片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う患者と片頭痛予防薬の 3 剤目の治療を中止した患者に大別される。費用対効果評価専門組織より、 片頭痛予防薬の 1 剤目はロメリジンと指定されているので、ロメリジン中止後にバルプロ酸および プロ プラ
ノロールを 2 剤目もしくは 3 剤目として使用して継続及び中止した患者の割合を C2H との NDBの共同解析より抽出した結果を以下の図 5-13 および表 5-11 に示す。
図 5-13 片頭痛予防治療薬のライン分析結果 (NDB 共同解析)

表 5-15 片頭痛予防薬の 2 剤目の治療又は 3 剤目の治療を行う患者と片頭痛予防薬の 3 剤
目の治療を中止した患者の割合（NDB 共同解析）
分析対象
集計項目
患者数
集団
2 剤目の
ロメリジン（中止）
91,418
治療又はロメリジン（中止）→バルプロ酸（継続）
2,463
3 剤目の
ロメリジン（中止）→プロプラノロール（継続）439
治療を行
ロメリジン（中止）→バルプロ酸（中止）
11,417
う患者
ロメリジン（中止）→プロプラノロール（中止）2,360
ロメリジン（中止）→バルプロ酸（中止）→プロプラノロール（継続）187

ロメリジン（中止）→プロプラノロール（中止）→バルプロ酸（継続）137

ロメリジン（中止）→バルプロ酸（中止）→プロプラノロール（中止）809

ロメリジン（中止）→プロプラノロール（中止）→バルプロ酸（中止）

498
総計

3 剤目の
治療を中
止した患
者

109,728

1 剤目としてロメリジンを中止した総患者数 109,728 人に対して、2 剤目の治療又は 3 剤目の145

治療を行う患者の割合はロメリジン中止後に実際は 2 剤目の治療を実施しなかった患者割合、 お
よび 2 剤目のバルプロ酸もしくはプロプラノロールの治療中止後に実際は 3 剤目の治療 を実施しなかった患者割合も含めて 98.8%であった。実際に 3 剤目としてプロプラノロールもしく はバルプロ酸による治療を実施した上で中止した患者の割合は 1.2%であった。
なお、本分析における 2 剤目の治療はプロプラノロールとしているが、科学院との合意により 2 剤
目にバルプロ酸を用いている患者も分析に含めた。

5.1.5.2 EM と CM の患者割合
本剤の処方対象患者が最適使用推進ガイドラインで限られていることから一般的な疫学デ ータより患者割合を出すことは不適切と考えられる。また、ヘルスケアシステムの違いから既に上 市している海外における本剤使用の実績から EM と CM の患者割合を日本で採用することもま た不適
切と考えられた。よって、

EM は 52.7%、CM は 47.3%であった。
表 5-16 調査概要
調査方法
標本台帳
調査地域
対象者条件

抽出方法
サンプルサイズ
実施期間

表 5-17て）

EM/CM 別人数と割合
EM, n (%)

CM, n (%)

146

5.1.5.3 価格調整率の重み
5.1.5.1 および 2 より、対象集団別の価格調整率の重みは以下のとおりである。
計算式
患者割合
対象集団
a 片頭痛予防薬の 2 剤目の治療又は 3 剤目 98.8%x52.7%
52.1%の治療を行う反復性片頭痛患者
b 片頭痛予防薬の 2 剤目の治療又は 3 剤目 98.8%x47.3%
46.7%の治療を行う慢性片頭痛患者
c
片頭痛予防薬の 3 剤目の治療を中止した反 1.2%x52.7%
0.6%
復性片頭痛患者
d 片頭痛予防薬の 3 剤目の治療を中止した慢 1.2%x47.3%
0.6%
性片頭痛患者
合計
100.0%
5.1.6 価格の引き上げ [該当する場合のみ]該当なし
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]
該当なし

5.3 その他の分析 [該当する場合のみ]
該当なし

147

6. 再分析用のデータ使用したソフトウェアMicrosoft
Excel and
VisualBasicforApplications

バージョン

ファイル名

提出メデ
ィア

Microsoft® Excel® forMicrosoft 365 MSO(Version 2109)
VBA:
7.1.1113
VBA7.1056160 Galcanezumab Migraine
CEM
Japan_FINAL_JP_10012022.xlsm

E メー
ル

148

7. 実施体制
名前：
所属：
役割：エムガルティの費用対効果評価実施に対する医療経済学的見地からの助言
利益相反： Eli Lilly Japan から本役割を含むアドバイザリ ー業務に対する委嘱料を受領
名前：
所属：
役割：エムガルティの費用対効果評価実施に対する臨床的見地からの助言
利益相反： Eli Lilly Japan から本役割を含むアドバイザリ ー業務に対する委嘱料を受領

149

8. 参考文献

Pharmaceutical and Medical Device Agency (PMDA) Emgality package insert,

1

2021. エムガルティ皮下注１２０ｍｇシリンジ.pdf
2

坂井文彦，福内靖男，岩田 誠，西村周三，濱田潤一，鈴木則宏，五十嵐久佳，清水俊彦，橋本しをり，望月温子：日本語版片頭痛用 quality of life 調査書の信頼性と妥当性の検討．神経治療 2004 ; 21（4）: 449-45
Takeshima T, Ishizaki K, Fukuhara Y, Ijiri T, Kusumi M, Wakutani Y, Mori M,

3

Kawashima M, Kowa H, Adachi Y, Urakami K, Nakashima K. Population-based
door-to-door survey of migraine in Japan: the Daisen study. Headache. 2004
Jan;44(1):8-19.
Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine

4

medications and evolution from episodic to chronic migraine: a longitudinal
population-based study. Headache. 2008 Sep;48(8):1157-68.
Manack A, Buse DC, Serrano D, Turkel CC, Lipton RB. Rates, predictors, and5consequences of remission from chronic migraine to episodic migraine.
Neurology. 2011 Feb 22;76(8):711-8.
国際頭痛学会. 京都頭痛宣言（2005 年）, 2005

6https://www.jhsnet.net/kyoto_2005.html
7

国際頭痛分類第 3 版（ICHD-3）日本語版（訳:日本頭痛学会・国際頭痛分類委員会）, 20148

頭痛の診療ガイドライン作成委員会（編）.日本神経学会・日本頭痛学会（監修）

頭痛の診療ガイドライン 2021. 東京: 医学書院;2021.
9慢性頭痛の診療ガイドライン作成委員会（編）. 日本神経学会・日本頭痛学会（監修）.

慢性頭痛の診療ガイドライン 2013. 東京: 医学書院; 2013.
10

Ministry of Health, Labor and Welfare (MHLW). Optimal used guidelines 最適

使用推進ガイドライン ガルカネズマブ（遺伝子組換え） （販売名：エムガルティ皮下注 120 mg
オートインジェク ター、エムガルティ皮下注 120 mg シリンジ）
https://www.mhlw.go.jp/content/12404000/000768564.pdf

150

11

Higgins, J.P.T. and S. Green. Cochrane Handbook for Systematic Reviews ofInterventions Version 5.1.0 [updated March 2011]. 2011; Available from:http://handbook.cochrane.org.
12

Moher, D., et al., The PRISMA Group. Preferred Reporting Items for

Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med,2009. 6(7): p.e1000097.
13

Goadsby, P.J., et al., Onset of ef f icacy and duration of response of

galcanezumab f or the prevention of episodic migraine: a post-hoc analysis.
Journal of Neurology, Neurosurgery & Psychiatry, 2019. 90(8): p. 939-944
14

Dodick, D.W., et al., Saf ety and ef f icacy of LY2951742, a monoclonal

antibody to calcitonin gene-related peptide, f or the prevention of migraine: aphase 2, randomised, double-blind, placebo-controlled study. Lancet Neurology,
2014. 13(9): p. 885-92.
15

Ayer, D.W., et al., Measures of Functioning in Patients With Episodic

Migraine: Findings From a Double-Blind, Randomized, Placebo-Controlled Phase
2b Trial With Galcanezumab. Headache, 2018. 58(8): p. 1225-1235
16

Skljarevski, V., et al., Ef f ect of Dif f erent Doses of Galcanezumab vs Placebo

f or Episodic Migraine Prevention: A Randomized Clinical Trial. JAMA Neurology,
2018. 75(2): p. 187-193.
17

Oakes, T.M., et al., Saf ety and tolerability of galcanezumab in a phase 2

migraine prevention study. Headache, 2017. 57 (Supplement 3): p. 190-191.
18

Detke, H.C., et al., Rapid Onset of Ef f ect of Galcanezumab f or the Preventionof Episodic Migraine: Analysis of the EVOLVE Studies. Headache, 2020. 60(2):p. 348-359.
19

Stauf f er, V.L., et al., Evaluation of Galcanezumab f or the Prevention of

Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. JAMA Neurology,
2018. 75(9): p. 1080-1088
20

Ford, J.H., et al., Two randomized migraine studies of galcanezumab: Ef f ects

on patient f unctioning and disability. Neurology, 2019. 93(5): p. e508-e517
21

Skljarevski, V., et al., Ef f icacy and saf ety of galcanezumab f or the prevention151

of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled
clinical trial. Cephalalgia, 2018. 38(8): p. 1442-1454.
22

Detke, H.C., et al., Galcanezumab in chronic migraine: The randomized,

double-blind, placebo-controlled REGAIN study. Neurology, 2018.
23

Mulleners WM, Kim BK, Láinez MJA, Lanteri-Minet M, Pozo-Rosich P, Wang S,

Tockhorn-Heidenreich A, Aurora SK, Nichols RM, Yunes-Medina L, Detke HC.
Safety and efficacy of galcanezumab in patients for whom previous migraine
preventive medication from two to four categories had failed (CONQUER): a
multicentre, randomised, double-blind, placebo-controlled, phase 3b trial.
Lancet Neurol. 2020 Oct;19(10):814-825.
24

Reuter U, Lucas C, Dolezil D, Hand AL, Port MD, Nichols RM, Stroud C,

Tockhorn-Heidenreich A, Detke HC. Galcanezumab in Patients with Multiple
Previous Migraine Preventive Medication Category Failures: Results from theOpen-Label Period of the CONQUER Trial. Adv Ther. 2021 Nov;38(11):54655483.
25

Sakai F, Ozeki A, Skljarevski V. Efficacy and safety of galcanezumab forprevention of migraine headache in Japanese patients with episodic migraine: A
phase 2 randomized controlled clinical trial. Cephalalgia Reports. January 2020.
26

Shibata M, Nakamura T, Ozeki A, Ueda K, Nichols RM. Migraine-SpecificQuality-of-Life Questionnaire (MSQ) Version 2.1 Score Improvement inJapanese Patients with Episodic Migraine by Galcanezumab Treatment: Japan
Phase 2 Study. J Pain Res. 2020 Dec 31;13:3531-3538.
27

Tatsuoka Y, Takeshima T, Ozeki A, Matsumura T. Treatment Satisfaction ofGalcanezumab in Japanese Patients with Episodic Migraine: A Phase 2
Randomized Controlled Study. Neurol Ther. 2021 Jun;10(1):265-278.
28

Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J, Masson M, Masson C,

Dry J, Koulikovsky G, Nguyen G, et al. Long-acting propranolol in migraine
prophylaxis: results of a double-blind, placebo-controlled study. Cephalalgia.
1989 Dec;9(4):247-53.
29

Mathew NT. Prophylaxis of migraine and mixed headache. A randomized

152

controlled study. Headache. 1981 May;21(3):105-9.
30

Ryan RE Sr. Comparative study of nadolol and propranolol in prophylactic

treatment of migraine. Am Heart J. 1984 Oct;108(4 Pt 2):1156-9.
31

Sargent J, Solbach P, Damasio H, Baumel B, Corbett J, Eisner L, Jessen B,

Kudrow L, Mathew N, Medina J, et al. A comparison of naproxen sodium topropranolol hydrochloride and a placebo control for the prophylaxis of migraine
headache. Headache. 1985 Sep;25(6):320-4.
32

Sudilovsky A, Elkind AH, Ryan RE Sr, Saper JR, Stern MA, Meyer JH.

Comparative efficacy of nadolol and propranolol in the management of migraine.
Headache. 1987 Sep;27(8):421-6.
33

Diener HC, Föh M, Iaccarino C, Wessely P, Isler H, Strenge H, Fischer M,

Wedekind W, Taneri Z. Cyclandelate in the prophylaxis of migraine: a randomized,
parallel, double-blind study in comparison with placebo and propranolol. The
Study group. Cephalalgia. 1996 Oct;16(6):441-7.
34Diener HC, Tfelt-Hansen P, Dahlöf C, Láinez MJ, Sandrini G, Wang SJ, Neto W,

Vijapurkar U, Doyle A, Jacobs D; MIGR-003 Study Group. Topiramate in migraine
prophylaxis--results from a placebo-controlled trial with propranolol as an active
control. J Neurol. 2004 Aug;251(8):943-50.
35

Ashtari F, Shaygannejad V, Akbari M. A double-blind, randomized trial of low-dose topiramate vs propranolol in migraine prophylaxis. Acta Neurol Scand. 2008
Nov;118(5):301-5.
36

Jafarpour M, Yousefi G, Hamedi A, Shariat A, Salehi A, Heydari M. Effect of a

traditional syrup from Citrus medica L. fruit juice on migraine headache: A
randomized double blind placebo controlled clinical trial. J Ethnopharmacol. 2016
Feb 17;179:170-6.
37

Dakhale GN, Sharma VS, Thakre MN, Kalikar M. Low-dose sodium valproate

versus low-dose propranolol in prophylaxis of common migraine headache: A
randomized, prospective, parallel, open-label study. Indian J Pharmacol. 2019
Jul-Aug;51(4):255-262.
38

Eli Lilly and Company (2019). Production reports.

153

39

Higgins JPT. and Green S. Cochrane Handbook for Systematic Reviews ofInterventions Version 5.1.0 [updated March 2011]. 2011; Available from:http://handbook.cochrane.org
40

Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect

treatment comparisons in meta-analysis of randomized controlled trials. J Clin
Epidemiol. 1997 Jun;50(6):683-91.
41

Di Tanna GL, Porter JK, Lipton RB, Brennan A, Palmer S, Hatswell AJ, Sapra

S, Villa G. Migraine day frequency in migraine prevention: longitudinalmodelling approaches. BMC Med Res Methodol. 2019 Jan 23;19(1):20.
42

Silberstein S, Tfelt-Hansen P, Dodick DW, Limmroth V, Lipton RB, Pascual J,

Wang SJ. Guidelines for controlled trials of prophylactic treatment of chronic
migraine in adults. Cephalalgia, 2008; 28(5):484-95.
43

Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D'Amico D, Diener HC,

Hansen J, Lanteri-Minet M, Loder E, McCrory D, Plancade S, Schwedt T.
International Headache Society Clinical Trials Subcommittee. Guidelines
for controlled trials of drugs in migraine. Third edition. A guide for investigators.
Cephalalgia, 2012;32:6-38.
44 National Institute for Health and Care Excellence (NICE). Fremanezumab forpreventing migraine [ID1368]. 2019a; Available from:https://www.nice.org.uk/guidance/indevelopment/gid-ta10339
45

National Institute for Health and Care Excellence (NICE). Galcanezumab forpreventing migraine [ID1372]. 2020; Available from:https://www.nice.org.uk/guidance/indevelopment/gid-ta10454/documents.
46

Ashina M, Goadsby PJ, Reuter U, Silberstein S, Dodick DW, Xue F, Zhang F,

Paiva da Silva Lima G, Cheng S, Mikol DD. Long-term efficacy and safety oferenumab in migraine prevention: Results from a 5-year, open-label treatment
phase of a randomized clinical trial. Eur J Neurol. 2021 May;28(5):1716-1725.
doi: 10.1111/ene.14715. Epub 2021 Jan 20.
47

National Institute for Health and Care Excellence (NICE). Erenumab forpreventing migraine [ID1188]. 2019b; Available from:154https://www.nice.org.uk/guidance/indevelopment/gid-ta10302/documents
48

National Institute for Health and Care Excellence (NICE). Botulinum toxin

type A for the prevention of headaches in adults with chronic migraine.
Technology Appraisal Guidance [TA260]. 2012
49

C2H, Guideline for Preparing Cost-Effectiveness Evaluation to the Central

Social Insurance Medical Council. Version 2.0 approved by CSIMC on 20th
February, 2019. guideline for cost-effectiveness evaluation in Japan(niph.go.jp).
50

Kikui S, Chen Y, Todaka H, Asao K, Adachi K, Takeshima T. Burden of

migraine among Japanese patients: a cross-sectional National Health andWellness Survey. J Headache Pain. 2020 Sep 10;21(1):110. doi:
10.1186/s10194-020-01180-9.
51

MHLW, 第 22 回生命表 (2015), https://www.e-stat.go.jp/stat-search/files?page=1&layout=datalist&toukei=00450012&tstat=000001031336&
cycle=7&tclass1=000001060864&tclass2=000001096035., 1 March 2017.
52

Briggs A, Sculpher M. An Introduction to Markov Modelling for Economic

Evaluation. PharmacoEconomics, 1998;13(4):397-409
53

Camporeale A, Kudrow D, Sides R, Wang S, Van Dycke A, Selzler KJ, Stauffer

VL. (2018). A phase 3, long-term, open-label safety study of Galcanezumab inpatients with migraine. BMC Neurol, 2018:18(1):188.
54

Hirata K, Takeshima T, Sakai F, Tatsuoka Y, Suzuki N, Igarashi H, Nakamura

T, Yamazaki H, Skljarevski V. A long-term open-label safety study ofgalcanezumab in Japanese patients with migraine. EXPERT OPINION ON DRUG
SAFETY, 2021;20(6):721-733.
55

Eli Lilly and Company. I5Q-MC-CGAI Clinical Study Report and IMPD. A Phase3, Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 in
Patients with Chronic Migraine – the REGAIN Study: Final Results from the
Double-Blind Treatment Phase and Interim Results from the Open-Label
Treatment Phase. 2017c.
56

Detke HC, Li LQ, Wang S, Aurora SK. One-year treatment with galcanezumab155

in patients with chronic migraine: Results from the open-label phase of the
REGAIN study. Cephalalgia, 2018;38(Suppl 1):149 [MTIS2018-178].
57

Gudmundsson LS, Scher AI, Aspelund T, Eliasson JH, Johannsson M,

Thorgeirsson G, Launer L, Gudnason V. Migraine with aura and risk ofcardiovascular and all cause mortality in men and women: prospective cohort
study. Bmj, 2010;341:c3966.
58

Asberg AN, Stovner LJ, Zwart JA, Slagsvold Winsvold B, Heuch I, Hagen K.

Migraine as a predictor of mortality: The HUNT study. Cephalalgia, 2016;
36(4):351-7.
59

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators,

Global, regional, and national incidence, prevalence, and years lived withdisability for 354 diseases and injuries for 195 countries and territories, 19902017: a systematic analysis for the Global Burden of Disease Study 2017.
Lancet, 2018;392(10159):1789-858.
60

Di Tanna GL, Porter JK, Lipton RB, Brennan A, Palmer S, Hatswell AJ, Sapra

S, Villa G. Migraine day frequency in migraine prevention: longitudinalmodelling approaches. BMC Med Res Methodol. 2019 Jan 23;19(1):20.
61

Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluationof Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1
Randomized Clinical Trial. JAMA Neurol. 2018 Sep 1;75(9):1080-1088.
62

Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy

and safety of galcanezumab for the prevention of episodic migraine: Results ofthe EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalagia,
2018;38:1442–54.
63

Detke HC, Li LQ, Wang S, Aurora SK. One-year treatment with galcanezumabin patients with chronic migraine: Results from the open-label phase of the
REGAIN study. Cephalalgia, 2018;38(Suppl 1):149 [MTIS2018-178].
64

Camporeale A, Kudrow D, Sides R, Wang S, Van Dycke A, Selzler KJ, Stauffer

VL. (2018). A phase 3, long-term, open-label safety study of Galcanezumab inpatients with migraine. BMC Neurol, 2018:18(1):188.

156

65

Mulleners WM, Kim BK, Lainez MJA, Lanteri-Minet M, Pozo-Rosich P, Wang S,

Tockhorn-Heidenreich A, Aurora SK, Nichols RM, Yunes-Medina L, Detke HC.
Safety and efficacy of galcanezumab in patients for whom previous migraine
preventive medication from two to four categories had failed (CONQUER): a
multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. The
Lancet. Neurology, 2020; Oct;19(10):814-825.
66

Ruff DD, Ford JH, Tockhorn-Heidenreich A, Stauffer VL, Govindan S, Aurora

SK, Terwindt GM, Goadsby PJ. Efficacy of galcanezumab in patients withepisodic migraine and a history of preventive treatment failure: results fromtwo global randomized clinical trials. Eur J Neurol. 2020 Apr;27(4):609-618.
67

Ruff DD, Ford JH, Tockhorn-Heidenreich A, Sexson M, Govindan S, Pearlman

EM, Wang SJ, Khan A, Aurora SK. Efficacy of galcanezumab in patients withchronic migraine and a history of preventive treatment failure. Cephalalgia.
2019 Jul;39(8):931-944.
68

Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis

adherence and persistence. J Manag Care Pharm. 2014 Jan;20(1):22-33.
69

Berger A, Bloudek LM, Varon SF, Oster G. Adherence with migraine

prophylaxis in clinical practice. Pain Pract. 2012 Sep;12(7):541-9.
70

Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence tooral migraine-preventive medications among patients with chronic migraine.
Cephalalgia. 2015 May;35(6):478-88.
71

Hepp Z, Dodick DW, Varon SF, Chia J, Matthew N, Gillard P, Hansen RN,

Devine EB. Persistence and switching patterns of oral migraine prophylactic
medications among patients with chronic migraine: A retrospective claims
analysis. Cephalalgia. 2017 Apr;37(5):470-485.
72

Yaldo AZ, Wertz DA, Rupnow MF, Quimbo RM. Persistence with migraine

prophylactic treatment and acute migraine medication utilization in the
managed care setting. Clin Ther. 2008 Dec;30(12):2452-60.
73

Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy

and safety of galcanezumab for the prevention of episodic migraine: Results ofthe EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalagia,
157

2018;38:1442–54.
74

Asberg AN, Stovner LJ, Zwart JA, Slagsvold Winsvold B, Heuch I, Hagen K.

Migraine as a predictor of mortality: The HUNT study. Cephalalgia, 2016;
36(4):351-7.
75

Gudmundsson LS, Scher AI, Aspelund T, Eliasson JH, Johannsson M,

Thorgeirsson G, Launer L, Gudnason V. Migraine with aura and risk ofcardiovascular and all cause mortality in men and women: prospective cohort
study. Bmj, 2010;341:c3966
76

Ruiz de la Torre E, Martelletti P, Craven A, Walsh D, Evans S, Dumas P, et al.

Real-world patient perspective on the burden and impact of migraine. J
Headache Pain. 2017;18:111.
77

Ruiz de Velasco I, Gonzalez N, Etxeberria Y, Garcia-Monco JC. Quality of life

in migraine patients: a qualitative study. Cephalalgia : an international journalof headache. 2003;23(9):892-900.
78

Walters AB, Hamer JD, Smitherman TA. Sleep disturbance and affective

comorbidity among episodic migraineurs. Headache. 2014;54(1):116-24.
79

Raggi A, Giovannetti AM, Quintas R, D'Amico D, Cieza A, Sabariego C, et al.

A systematic review of the psychosocial difficulties relevant to patients with
migraine. J Headache Pain. 2012;13(8):595-606.
80

Ruiz de Velasco I, Gonzalez N, Etxeberria Y, Garcia-Monco JC. Quality of life

in migraine patients: a qualitative study. Cephalalgia : an international journalof headache. 2003;23(9):892-900.
81

Ford JH, Jackson J, Milligan G, Cotton S, Ahl J, Aurora SK. A Real-World

Analysis of Migraine: A Cross-Sectional Study of Disease Burden and Treatment
Patterns. Headache. 2017;57(10):1532-44.
82

Vo P, Paris N, Bilitou A, Valena T, Fang J, Naujoks C, et al. Burden of Migraine

in Europe Using Self-Reported Digital Diary Data from the Migraine Buddy(c)Application. Neurol Ther. 2018;7(2):321-32.
83

Burgess SM, Gauthier M, Cala ML. Comparison of Patient-Reported Outcomes

Requirements in Medical Guidelines for Pain, Migraine, Rheumatoid Arthritis,158

and Systemic Lupus Erythematosus: Europe Vs. United States. Value in Health.
2015;18(7):A743.
84

Linde M, Dahlof C. Attitudes and burden of disease among self-considered

migraineurs--a nation-wide population-based survey in Sweden. Cephalalgia :an international journal of headache. 2004;24(6):455-65.
85

Chaushev N, Milanov I. Impact of migraine and migraine treatment onpatient’s capacity to work and quality of life. J Clin Med. 2009;2:26-31.
86

Lampl C, Thomas H, Stovner LJ, Tassorelli C, Katsarava Z, Lainez JM, et al.

Interictal burden attributable to episodic headache: findings from the Eurolight
project. J Headache Pain. 2016;17:9.
87

Steiner TJ, Stovner LJ, Katsarava Z, Lainez JM, Lampl C, Lanteri-Minet M, etal. The impact of headache in Europe: principal results of the Eurolight project.
J Headache Pain. 2014;15:31.
88

Lipton RB, Buse DC, Sandoe CH, Ford JH, Hand AL, Jedynak JP, et al.

Interictal burden of migraine: correlations with other measures of migraine
burden and effects of galcanezumab migraine-preventive treatment. 14th
European Headache Federation Virtual 2020.
89

Raggi A, Giovannetti AM, Quintas R, D'Amico D, Cieza A, Sabariego C, et al.

A systematic review of the psychosocial difficulties relevant to patients with
migraine. J Headache Pain. 2012;13(8):595-606.
90

Jhingran P, Osterhaus JT, Miller DW, Lee JT, Kirchdoerfer L. Development andvalidation of the Migraine-Specific Quality of Life Questionnaire. Headache.
1998 Apr;38(4):295-302.
91

Jhingran P, Davis SM, LaVange LM, Miller DW, Helms RW. MSQ: Migraine-

Specific Quality-of-Life Questionnaire. Further investigation of the factor
structure. Pharmacoeconomics. 1998 Jun;13(6):707-17.
92

Martin BC, Pathak DS, Sharfman MI, Adelman JU, Taylor F, Kwong WJ,

Jhingran P. Validity and reliability of the migraine-specific quality of life
questionnaire (MSQ Version 2.1). Headache. 2000 Mar;40(3):204-15.
93

Bagley CL, Rendas-Baum R, Maglinte GA, Yang M, Varon SF, Lee J, Kosinski
159

M. Validating Migraine-Specific Quality of Life Questionnaire v2.1 in episodic andchronic migraine. Headache. 2012 Mar;52(3):409-21.
94

Speck RM, Shalhoub H, Ayer DA, Ford JH, Wyrwich KW, Bush EN. Content

validity of the Migraine-Specific Quality of Life Questionnaire version 2.1
electronic patient-reported outcome. J Patient Rep Outcomes, 2019; 3(1):39.
95

Gillard PJ, Devine B, Varon SF, Liu L, Sullivan SD. Mapping from disease-specific measures to health-state utility values in individuals with migraine.
Value Health. 2012 May;15(3):485-94.
96

Longworth L, Rowen D. Mapping to obtain EQ-5D utility values for use in

NICE health technology assessments. Value Health. 2013 Jan-Feb;16(1):20210.
97

Griffiths A, Paracha N, Davies A, Branscombe N, Cowie MR, Sculpher M.

Analyzing health-related quality of life data to estimate parameters for costeffectiveness models: an example using longitudinal EQ-5D data from theSHIFT randomized controlled trial. Advances in Therapy, 2017;34(3):753–64.
98

Ministry of Health, Labor and Welfare (MHLW),

https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000188411_00033.html

160