Copyright © 2018 Covance. All Rights Reserved

Histories of ICH-GCP Implementation, Clinical Trial
Notification, and Clinical Trial Consultation in Japan
FY1997

J-GCP (revised)[ICH-GCP concept]
Clinical Trial
Notification (revised)

Clinical Trial
Consultation
In East Asia, the ICH GCP wasadopted in Japan in 1997, inKorea in 2001, in Taiwan in2002, and in China in 2003
respectively.

FY2003 FY2004

ICH-GCP “E6 (R1)” was globally introduced in 1996.

Handled byHandled by

Pharmaceuticals and Medical
Devices Evaluation Center(PMDEC)

Pharmaceuticals andMedical Devices Agency(PMDA)Handled byHandled by

Organization for
Pharmaceutical Safety andResearch (OPSR or “KIKO”)

Pharmaceuticals andMedical Devices Agency(PMDA)

Tetsuomi Takano, Covance Japan (Tokyo, 17/Jan/2018)

PMDA-ATC MRCT Seminar 2018 (APEC Center of Excellence Workshop)2

医薬品登録管理弁法 (SFDA局令第28号, 2007/10/1施行)
第44条 国際共同治験 ←2002/12/1施行の試行版より記載有り

 かつて国産薬のMRCTは認められていなかった。
 かつて輸入薬のP1(～P2)のMRCTに中国を参加させることはできなかった。

3◊2005-2010.12◊Global clinical trial applications of small molecular products
2005-2010抗肿瘤药国际多中心适应症分布结直肠

3申报数量胃癌

7

肾癌12

肝癌

15

血液肿瘤类型18乳腺癌

22NSCLC

3105101520253035

肿瘤类型*2005-2010.12 total applications of small molecular products on oncology
were 152. 123 of them were approved.
Yang Zhimin, CDE, SFDA, China (APEC MRCT Tokyo Workshop, 02/Nov/2011)55

•

Under the China Association of Enterprises with Foreign Investment (CAEFI), the R&D-based
Pharmaceutical Association Committee (RDPAC) is a non-profit organization made up of 40
member companies with pharmaceutical R&D capability.
RDPAC is member of International Federation of Pharmaceutical Manufacturers &Associations (IFPMA).
(Source: RDPAC website)•6| 第8回がん新薬開発シンポジウム | 5 Oct 2018

Outline of the Opinions of the State Council on Reforming the Evaluation
and Approval System for Drugs and Medical Devices (State Council Doc
2015 No.44, 18/Aug/2015) and the China Regulatory Reform
Chinese government website: http://www.gov.cn/zhengce/content/2015-08/18/content_10101.htm
Japanese translation by CCFDIE: http://www.cjpi.org.cn/zryyxxwjp/zxdt/webinfo/2017/01/1485778118968067.htm
http://www.cjpi.org.cn/zryyxxwjp/scxx/zhxx/webinfo/2015/08/1485778130567129.htm

3-year reform plan initiated by China’s State Council to reform the evaluation
and approval system for drugs and medical devices since August 2015
Key Objectives

Key Objectives► Improve the quality of review and approval

5► Resolve the backlog of registration applications► Improve the quality of generic drugs

4

12

Safeguard
Measures

Major Tasks

2015

李克强
Lǐ Kèqíang(01/Jul/1955-)► Encourage research and innovation► Increase review and approval transparency

Faster and more improved & transparent processes
for innovative drugs
2016

2017

2018

5 new registration categories for chemical drugs were defined in Mar 2016.
Still updating; still partially under discussion and unclear;need close observation and discussion
10| 第8回がん新薬開発シンポジウム | 5 Oct 2018

第12次5カ年計画(2011-2015)2011年、中国政府は第12次5カ年計画(2011-2015)でバイオ医薬品産業を国家の基幹産業に育成すると発表
中国政府方針 高度先進技術のバイオ医薬品産業を育成し、中国発の大型新薬開発を進める 世界の工場から、世界の市場、世界の研究機関の中心へ
 人材育成 (大学・研究機関を充実させ、優秀な人材の育成・海外の人材招聘)
 新しい製品・技術の開発と導入 (原材料輸出から付加価値の高い 製品輸出へ転換)
政府主導の支援政策
 バイオ医薬は重点発展分野に入る、2020年までバイオ医薬強国を目指す バイオ医薬技術企業に対し減税(研究費用50％免税、所得税15％まで下げる)
 第十二期五ヶ年計画（2011-15年）期間中、バイオ新薬の開発に400億元資金を投入予定[出典：正田豊, 中国における医療制度改革と医療行政 (東京, 2012/7/10)]

第13次5カ年計画(2016-2020)
バイオ医薬品産業は、以後数年間で中国政府の重点支援を受けて急成長 2010年～2014年のバイオ医薬品産業における製造業の売上高の年平均成長率は23%以上
 2020年には中国のバイオ医薬品市場は米国に次いで世界第2位へ
12| 第8回がん新薬開発シンポジウム | 5 Oct 2018

Founded in 1988, China Pharmaceutical Innovation and Research Development
Association (PhIRDA) is registered as a non-profit organization by the Ministry of Civil
Affairs of China at the first national level.
•PhIRDA will exert great effort on “academia-industry collaboration”, which centers on theprinciple of “innovation, industrialization, internationalization”, persists in innovation toachieve unmet clinical requirements.
At current stage, PhIRDA has 142 members, mainly consist of five major categories: First,
start-up and R&D enterprises focusing on innovation of pharmaceutical products; Second,domestic first-class universities, colleges and research institutions conducting
pharmaceutical research and development; Third clinical institutions featuring high skills inapplicable research on new drugs, especially those undertake “major new drug innovation”
technological platform for good clinical practice; Fourth, investment institutions committing topharmaceutical innovation; Fifth, national pharmaceutical enterprises excelling at innovation.
PhIRDA is also a member of International Federation of Pharmaceutical Manufacturers &Associations (IFPMA) to continuously broaden channels of international collaboration.

••
13| 第8回がん新薬開発シンポジウム | 5 Oct 2018

(Source: PhIRDA website)• China BioMed Innovation and Investment Conference (CBIIC) was established on
November 14, 2016 by China Pharmaceutical Innovation and Research
Development Association (PhIRDA), China Association for Medical Devices
Industry (CAMDI) and Hong Kong Exchange and Clearing Limited (HKEX).
• Aiming to build an authorized platform of collaboration and integration forpharmaceutical innovative enterprises, investors and capital at home and abroad,
CBIIC has drawn more than 3500 participants, over 700 pharmaceutical industries
and 500 financial institutions, including government officials, senior executives andexperts in pharmaceutical industry and representatives from media.
17| 第8回がん新薬開発シンポジウム | 5 Oct 2018

Source: http://2018cbiic.phirda.com/

Announcement on Pilot Program of Drug MAH (MarketingAuthorization Holder) System
The MAH pilot program in China has been started since 06/Jun/2016.
JP Pharmas should also need to consider the next step.
[Extract from EN Translation for the announcement from the General Office of the State Council
No. [2016] 41 (Released on 06/Jun/2016)]
http://www.gov.cn/zhengce/content/2016-06/06/content_5079954.htm
 Pilot Scope- Districts: 10 provinces or municipalities including Beijing 北京, Tianjin 天津, Hebei 河北, Shanghai 上海,Jiangsu 江蘇, Zhejiang 浙江, Fujian 福建, Shandong 山東, Guangdong 広東, and Sichuan 四川- Pharmaceutical Products:
It covers chemical drugs, biological products, traditional Chinese medicines and natural drugs.
① New drugs: According to current DRR chemical drugs registration category 1-4, part of category 5; biologicalproducts registration category 1, 7 and biosimilar; new registration category of chemical drugs 1-2② Generic drugs approved based on the new standard of quality and efficacy consistent evaluation with original
drugs: New registration category of chemical drugs 3-4③ Marketed pharmaceutical products: Have passed the consistency evaluation; manufacturing site change.
 Pharmaceutical research and development institution or researcher in the Districts can be a MAH.
 Submission documents: Qualification certificates, drug qualify and safety responsibility commitment
 Obligations and responsibilities of MAH and contracted manufacturer
 Application of MAH- Newly registered products: Simultaneous application for being MAH with NDA- Marketed products: Supplemental application for being MAH and contracted manufacturing Implementation period is from Jun. 6, 2016 to Nov. 4, 2018.
 Drug manufacturers in the Districts can implement by referring to the requirements on MAH in the pilot program.
Tetsuomi Takano, 91st JPMA Asia Committee Meeting (Tokyo, 15/Jul/2016)

18

E-Journal on Requirements of Clinical Part Documentsfor FIH Clinical Trial Application of Oncology New Drugs(by Chen Xiaoyuan, CDE; Released by CDE on 08 Feb 2018)► Background: Oncology new drugs are hot spots for global innovation drug research,accounting for approximately 40% of current innovation drug clinical trial applications.
However, at the present stage of the FIH application for oncology drugs, the submitted
clinical trial programs had some problems such as uneven levels, lack of important
content, and poor program operability. In order to encourage innovation and practicalimplementation of the "Opinions" of the two offices, the Chemical Clinical I Department ofCDE has discussed the preparations for the application of clinical data for the first-inhuman clinical trials of oncology new drugs.
► General Requirements:

1. Overall R&D Plan
2. Clinical Study Protocol (2.1 – 2.18)
3. Clinical Study Protocol Supporting Documents(3.1 Overall Clinical Summary, 3.2 Independent Risk Management Plan, 3.3 IB,
3.4 ICF, 3.5 EC status, 3.6 Others)
CDE website: http://www.cde.org.cn/dzkw.do?method=largePage&id=314311(Supported by RDPAC for English translation)

19| 第8回がん新薬開発シンポジウム | 5 Oct 2018

E-Journal on General Requirements of NDA/BLADossier for Anti PD-1/PD-L1 Monoclonal Antibody(by Zhang Hong, CDE; Released by CDE on 08 Feb 2018)► Including the 5 anti-PD-1/PD-L1 monoclonal antibodies marketed worldwide [Keytruda(Pembrolizumab), Opdivo (Nivolumab) / Tecentriq (Atezolizumab), Bavenci (Avelumab)
and Imfinzi (Durvalumab)], there have been 16 similar products in China to obtain clinicalapproval, and carry out clinical trials in different tumor types. However, as of now, no antiPD-1 or PD-L1 monoclonal antibody has been approved in China.
► CDE held a symposium on relevant product application information requirements in Beijing

on 12 Jan 2018. To meet urgent unmet medical needs of advanced cancer patients,
shorten NDA/BLA review periods, and accelerate market access of anti-PD-1/PD-L1
monoclonal antibodies in China, CDE would newly initiate accelerate approval withsurrogate endpoint of Objective Response Rate (ORR) and rolling submission system atNDA/BLA review stage for the first time in China. Actual procedures for each NDA/BLA
product of anti-PD-1/PD-L1 monoclonal antibodies will be discussed at Pre-NDA meeting
between CDE and sponsor/applicant.
► Detailed Requirements for Rolling Submission Dossiers at (I) Initial submission, (II) During

the NDA review, and (III) Final submission before NDA approval were also disclosed on theCDE website.
CDE website: http://www.cde.org.cn/dzkw.do?method=largePage&id=314347(Supported by RDPAC for English translation)

20| 第8回がん新薬開発シンポジウム | 5 Oct 2018

“CAR-T” and “recruiting or not yet recruiting” atClinicalTrials.gov (as of 12 Sep 2018)
Country/Region# ofstudies

Country/Region# ofstudies

Country/Region# ofstudies

Japan1

UK

9US

121

China

156

France12Canada

18

Hong Kong

0

Germany

4

Brazil4

Taiwan

1

Swiss

2

South Africa

3

Korea

0

Italy

6

Singapore

1

Spain

8

Australia

2

Sweden1

Russia1

22| 第8回がん新薬開発シンポジウム | 5 Oct 2018

(Source: ClinicalTrials.gov)

 The establishment of 38 expert advisory committees with each number of experts
was proposed.
 The preliminary list of 630 experts was announced (Attachment 2).
1马军哈尔滨血液病肿瘤研究所8吴一龙广东省人民医院肺癌研究所2

王建祥

中国医学科学院天津血液病研究所白血病诊疗中心9

沈琳

北京大学肿瘤医院消化肿瘤内科

10

郞锦义

四川省肿瘤医院肿瘤放疗中心

11

秦叔逵

解放军南京八一医院全军肿瘤中心

12

徐兵河

中国医学科学院肿瘤医院内科

13

徐瑞华

中山大学肿瘤医院内科

14

郭军

北京大学肿瘤医院
肾癌黑色素瘤内科

15韩宝惠

上海市胸科医院呼吸内科

3毛颖复旦大学附属华山医院神经外科4石远凯

中国医学科学院肿瘤医院内科

5卢铀

四川大学华西医院胸部肿瘤科

6江泽飞军事医学研究院附属医院
乳腺肿瘤科

7

吴炅

复旦大学附属肿瘤医院乳腺外科

CDE website: http://www.cde.org.cn/news.do?method=viewInfoCommon&id=314275
23| 第8回がん新薬開発シンポジウム | 5 Oct 2018

医師名所属

癌種試験数

4

石远凯

中国医学科学院肿瘤医院内科

固形癌, 肺癌, リンパ腫等

61

11

秦叔逵

解放军南京八一医院全军肿瘤中心肝細胞癌等

4412徐兵河中国医学科学院肿瘤医院内科

固形癌, 乳癌等

408吴一龙广东省人民医院肺癌研究所

肺癌等

38

9沈琳

北京大学肿瘤医院消化肿瘤内科

固形癌, 胃癌(含接合部), 食道癌等

3813

徐瑞华

中山大学肿瘤医院内科

固形癌, 大腸癌, 胃癌(含接合部)等

2914

郭军

北京大学肿瘤医院
肾癌黑色素瘤内科

黒色腫, 尿路上皮癌, 腎細胞癌等

272

王建祥

中国医学科学院天津血液病研究所白血病诊疗中心白血病, 多発性骨髄腫等

156

江泽飞

军事医学研究院附属医院
乳腺肿瘤科

乳癌

14

CDE website: http://www.cde.org.cn/news.do?method=viewInfoCommon&id=314275
24| 第8回がん新薬開発シンポジウム | 5 Oct 2018

2018/8/8、CDEは海外上市済かつ中国で臨床上緊急ニーズのある新薬リスト(48品目)のパブコメを開始（8/18まで）
No.

Product Name(Active ingredient)Company Name(MAH)

Place ofFirst
Approval

First approvaldate in EU, USor Japan

Therapeutic
Area

Therapeutic target

1

Alectinib
Hydrochloride

ChugaiJapan

2014/7/4

Tumor

ALK, RET

2

Pembrolizumab

MSD

US

2014/9/4

Tumor

PD-1

3

Olaparib

AstraZeneca

EU

2014/12/16

Tumor

PARP-1, PARP-2, PARP-3

11

Denosumab

Amgen Europe

EU2010/5/26

Tumor

RANKL

14

Ponatinib

Ariad PharmaUS

2012/12/14

Tumor

EPH receptor, FGFR, Src,
VEGFR, Kit, FLT-3,PDGFR, VEGFR, TIE2,RET

18

Palbociclib

PfizerInc

US2015/2/3

TumorCDK4; CDK620

Enasidenib mesylate

CelgeneUS2017/8/1

Tumor

IDH223Vismodegib

GenentechUS

2012/1/30

Tumor

SMO

33

Dinutuximab

United Therapeutics

US

2015/3/10

Tumor

GD2

34

Sonidegib

Novartis

US

2015/7/24

Tumor

SMO

35

Olaratumab

LillyUS

2016/10/19

Tumor

-38

Dinutuximab Beta

EUSA Pharma (UK)EU

2017/5/8

Tumor

GD2

CDE website: http://www.cde.org.cn/news.do?method=viewInfoCommon&id=314651
26| 第8回がん新薬開発シンポジウム | 5 Oct 2018

中国における抗がん剤等開発環境の変遷
年

主な出来事(施行日等)-2003

SDA設立(1998)； 輸入薬のP3 MRCT解禁(2002/12/1)； 当局組織改変SDA→SFDA(2003/4)； 中国にてICHGCP施行(2003/9/1)

2006

Icotinib P1 IND承認

2007

現行医薬品登録管理弁法(SFDA局令第28号)施行(10/1)

2011

第12次5カ年計画(政府主導のバイオ医薬品産業育成支援,2011-2015)； Icotinib承認(11M)2012

Pre-INDやPre-NDAを含むCDE communication meeting導入(7/16)

2013

当局組織改変SFDA→CFDA(3/22)； 低分子輸入薬でP(1-)2 MRCT実績(5月頃)； 輸入薬の三申請三承認制
度適用開始(12/23)

2015

CFDA MRCT Guideline施行：国産薬のMRCT解禁か(3/1)； 国務院第44号令(8/18)：中国薬事規制改革開始

2016

第13次5カ年計画(政府主導のバイオ医薬品産業育成支援,2016-2020)； 抗がん剤等対象の優先審査制
度開始(2/26)； 新薬の独自定義・化学薬品新分類施行(3/4)； MAH Pilot Program開始(6/6)

2017

Osimertinib承認(3月, 7M)； 中国ICH入り(6/1)； ワクチン製剤を除き輸入薬のMRCTをP1から解禁，輸入薬の三申請三承認制度を廃止(10/10)

2018

当局組織改変CFDA→CNDA(3/17)； 全ての輸入抗がん剤の関税を免除(5/1)； 中国ICH管理委員会入り(6/7)； Nivolumab承認(6月, 7M)； Pembrolizumab承認(7月, 5M)； 海外臨床試験データ受け入れの技術ガイドラインを制定(7/10)； IND審査制度を治験届制度に変更(7/27)； 海外上市済かつ中国で臨床上緊急ニーズのある新薬リスト(48品目)のパブコメ(8/8-18)； 当局の英語名称がNMPAに変更(9/1)； 中国にてICH-E17施行予定(12月)27| 第8回がん新薬開発シンポジウム | 5 Oct 2018

1.

中国のかつての巨大ジェネリック企業は、低分子だけでなくバイオ医薬品も手がける新薬メーカーに変身している。豊富な資金力を背景に人材や抗がん剤パイプラインを充実させている。

2.

中国には、人材、抗がん剤パイプライン(低分子+Immuno-oncology+α) を豊富に持ち、それら複数治験薬の多癌種、多レジメンのP1～P3試験を中国・米国・グローバルで一斉に一気に押し進めることのできる資金力を有するバイオベンチャーが多く存在する。

3.

中国政府は、中国をバイオ医薬強国、世界の研究機関の中心にするべく、バイオ医薬品産業への重点支援を行っている。

4.

中国政府は、国内の医薬品産業育成ばかりでなく、世界同時開発の最先端の輸入抗がん剤の中国での治験実施ならびに中国への上市を優遇している。

5.

中国は米国に次ぐ世界第2位の医薬品市場を有する。ジェネリックの比重は依然として高いものの、高額抗がん剤の支払い能力も見込まれている。

6.

CMOを用いたMAH制度導入、中国国産薬に対するMRCT解禁、輸入薬に対するP1stageからのMRCT解禁、治験届制度導入によるIND審査期間の劇的短縮、優先審査制度導入等によるNDA審査期間の劇的短縮など種々の規制緩和により、中国内外の製薬企業・バイオベンチャーにとって、中国での抗がん剤開発・上市の重要性は近年急上昇している。

7.

中国で国家を代表するようなKOLs, key investigatorsには、国内外から抗がん剤治験が押し寄せ、かつてないほどの治験競合状況となっている。

28| 第8回がん新薬開発シンポジウム | 5 Oct 2018

Acknowledgments► R&D-based Pharmaceutical Association Committee (RDPAC)► RDPAC Regulatory Affairs/Intelligence Working Groups► China Center for Food and Drug International Exchange (CCFDIE)► Pharmaceuticals and Medical Devices Agency (PMDA)► Japan Pharmaceutical Manufacturers Association (JPMA)29| 第8回がん新薬開発シンポジウム | 5 Oct 2018

THANK YOU

Covance Inc., headquartered in Princeton, NJ, USA, isthe drug development business of Laboratory
Corporation of America Holdings (LabCorp). COVANCE
is a registered trademark and the marketing name forCovance Inc. and its subsidiaries around the world.

30 | 第8回がん新薬開発シンポジウム | 5 Oct 2018