1

Clinical Trial Promotion and Medical Devices

Daisaku SatoR&D Division, Health Policy Bureau

Ministry of Health, Labour & Welfare

2

Earlier access: Development in Japan starts without much delay these days

1980 1985 1990 1995 2000 2005 2010

Today

Compound AWest Japan

Compound B

Compound C

Compound D

Compound E

Compound F

Compound G

Compound H

Compound IPhaseⅠstart to NDA

Source: Pfizer Japan

By courtesy of Yoshihiko Ono (Pfizer):

3

R&D Promotion of Drugs and Medical DevicesR&D Promotion of Drugs and Medical Devices

•• Speed of accessibility to patientsSpeed of accessibility to patients

–– Japanese patientsJapanese patients’’ accessibility to Japan originated innovationaccessibility to Japan originated innovation

–– Japanese patientsJapanese patients’’ accessibility to foreign originated products in a timely accessibility to foreign originated products in a timely manner, without delaymanner, without delay

←← Accessibility is not confined to approval, but clinical trial opAccessibility is not confined to approval, but clinical trial opportunityportunity

•• Quality, Cost and Speed of clinical trials and product review prQuality, Cost and Speed of clinical trials and product review process ocess in Japanin Japan

–– Does JapanDoes Japan’’s trial environment (quality, cost and speed) cope with s trial environment (quality, cost and speed) cope with foreign clinical trials?foreign clinical trials?

–– Has Japan developed the trial and review capacity, which attractHas Japan developed the trial and review capacity, which attracts s priority development/copriority development/co--development of innovative products in Japandevelopment of innovative products in Japan

Challenge to improvement of trial cost structure

4

Process R&D to marketing

2～3years

3～7Years

3～5years

1～2years

Non-clinical tests

Basic Research

Clinical trials

Review process

Pricing

&LaunchPMS

（出典）日本製薬工業協会ＨＰを厚生労働省にて加工

R&D Success

Number Of

Entities 406,753 235 36－ －

CumurativeSuccess Rate

1:1,731 1:11,2991 － －

（出典）日本製薬工業協会（国内企業18社の例：1995～1999年）

5

From Clinical research to Product

ProductReviewClinical Trials

Clinical Research

Clinical TrialEnvironment（Path）

Capacity

Review System（Pull）

Capacity

Clinical Research Environment（Push ）Capacity

6

Rising Cost of Drug DevelopmentRising Cost of Drug Development

7

Where Japanese companies conduct clinical trials

厚生労働省

4533

5859

2370

0

20

40

60

80

100

120

140

160

180

1993 2000

MEs

Foreign DevelopmentPriority

Japan-Foreign Co-development

Japan DevelopmentPriority

8

Challenges of Clinical TrialsThe following factors have been characterized:

１．Incentive driving subject (patient)> general recognition hurdle

> Universal insurance coverage vs. trial

２．Incentive driving investigator> Lower academic appraisal for clinical research

> Low economic insentive

３．Trial site capacity> Training and resources of investigators, CRCs

４．Shortage of investigator/institutions provision> lack of competition

Slow

Low Quality

Cost much

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Comparison of clinical trial environment between US/EU and JapanComparison of clinical trial environment between US/EU Comparison of clinical trial environment between US/EU and Japanand Japan

Development cost / subject No. of subject/ institution/ month Trial period

JPN EU US US EU and other 21 countries

JPN

US

JPN

10

Monitor Performance comparison

0

20

40

60

80

100

120

140

160

180

0

5

10

15

20

25

Subjects/ monitor Institutions/monitor

JPN US EU JPN US EU

(某製薬会社資料）

11

Cost comparison among sites under same protocol

Cost comparison among sites under same protocol

60

US$

000

's

0

10

20

30

40

50

Others Korea HK EU US JPN

代謝性疾患

Direct trial cost Subject recruitment/ad.

Clinical tests CRO others

島谷克義；第3回北里ハーバードシンポジウム、2003

（１） Clinical trial networking

（２） Site capacity building

（３） Supporting subject participation (enrollment)

training clinical research coordinator (CRC) （4,500 per. completed course）

“Mega trial network” （1,215 institutions）Sponsor-investigator trial support (12 trials)

General knowledge development （symposium, MHLW website, etc.）

（５） Clinical research promotion Clinical research base development project (2005-)Ethics Guideline of General Clinical Research

（４） Company’s expense reductionStandardization of contract formatDevelopment of PMDA’s consultation capacity

●●””Clinical Trial Promotion Clinical Trial Promotion 3 yearly3 yearly Action PlanAction Plan””2003 MEXT and MHLW

13

273

10931215

799

0

200

400

600

800

1000

1200

1400

2003 2004 2005 2006 as of Sept.

●●Mega trial network registered institutionsMega trial network registered institutions（機関）

14

●● Training completed Training completed CRCsCRCs

2468

3178

3877

4524

0

1000

2000

3000

4000

5000

2002 2003 2004 2005

（人）

Fiscal year

文部科学省、厚生労働省、日本看護協会、日本病院薬剤師会、日本臨床衛生検査技師会の平成１０年度以降ＣＲＣ養成研修終了者数の累計。

Changing Trial Site EnvironmentChanging Trial Site Environment

○ CRC disposition 66.3% → 97.4%○ Frequency of visit until contract conclusion

less than 6 times 26.0%→ 43.1%○ Duration of SDV procedure

same day or less than a week 64.8% → 77.8%Reference：EFPIA

調査方法： 今回：2004年及び2005年に第Ⅱ相及び第Ⅲ相臨床試験を開始した医療機関の実態に関するアンケ－トを実施前回：2002年及び2003年上半期に第2相及び第Ⅲ相臨床試験を開始した医療機関の実態に関するアンケ－トを実施なお、本集計結果は暫定的な集計結果であり、今後変更がありうるものである。

2002/2003 2004/2005

83

84

472

442

0 100 200 300 400 500 600

2003

2004

依頼～治験薬交付 治験薬交付～CRFクリーン

Trial Duration2003 av. 555 days

↓2004 av. 526 days

Reference: JPMA2003:2002年4月～2003年3月に終了した治験35課題のデータ2004:2003年4月～2004年3月に終了した治験31課題のデータ

Cost paid at clinical trial sites（研究経費、CRC費用、SMO費用を含む） 平均 195万円 → 167.8万円出典：Research on Clinical Cost R&D Head Club cost research working group 調査方法：製薬企業17社が実施した第Ⅱ相・第Ⅲ相の実施機関やコストについて調査した

2005年：2001年8月1日～2005年4月30日に実施された治験29課題、604施設のデータ2004年：1999年11月1日～2004年3月31日に実施された治験28課題、917施設のデータ

15

16

95

71

54 52

96

566060

43

63

722

500497

414361

438424

463

391406

0

50

100

150

200

250

300

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

0

100

200

300

400

500

600

700

800

●● No. of IND Notification to MHLWNo. of IND Notification to MHLW

年

First IND IND

New GCP

New GCP enacted

ICH E5

First IND

IND

Clinical Trial Promotion Action Plan

（厚生労働省調べ）

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１．１．Capacity Building of InstitutionCapacity Building of Institution・Developing Horizontal Networking (Core Clinical Research Centers and Major Clinical Trial Centers)・Local/Vertical Networking・Subject/Patient Panel・IRB System etc.

２．２．Training StaffTraining Staff・Investigator’s training and maintenance・Bio-statistician and data manager training and maintenence・CRC training and maintenance・Secretarial staff training etc.

３．３．Promotion of Subject RecruitmentPromotion of Subject Recruitment・Promotion/enlightenment activity・Promotion information（such as Trial registration database, etc.） etc.

４．４．CompanyCompany’’s Efficiency Improvements Efficiency Improvement・Format standardization・Introduction of IT and data communication format・Clarifying Role of sponsor and investigator/institution・Reducing workload of Monitor/auditor etc.

５．５．Drug and Device Clinical Research PromotionDrug and Device Clinical Research Promotion・General Clinical Research Capability etc.

Challenges for Next Trial Action PlanChallenges for Next Trial Action Plan

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Scheduling for next action planClinical Trial Promotion 3 yearlyClinical Trial Promotion 3 yearly Action PlanAction Plan （2003-2005 FY） extension

Study Committee Surveillance WGs：

現在開催中 （平成１８年６月～）

Regulatory study committee

次期全国治験活性化５カ年計画作成のための検討

Target Implementation April 2007

Next clinical trial promotion action plan

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Status surveillance report: Clinical Trial NetworkingStatus surveillance report: Clinical Trial Networking

Answered by 64 networks including SMOs

Current clinical trial networks do not necessarily function as they are expected

‒ Half of the networks have not contracted trial.

‒‒ Only 50% of network secretariats recruit CRC. Only 50% of network secretariats recruit CRC.

‒‒ 30% of the institutions feel No. of CRC insufficient. 30% of the institutions feel No. of CRC insufficient.

‒ 50-60% of the institutions,the institutions, Central IRB is in place.

‒ Common contract format >50%

‒ Unified data management 50-60%

– 60% of the network depend on SMO.‒ 80% of the network and SMOs hold common subject database.

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•• MDsMDs– MDs seek incentive of perform trials in contribution to medical development, getting grant,

catching up new medical information.– MDs feels disincentive, due to “busy with work”, “less appraised”, “less recognized by

colleague and patient”•• ＣＲＣＣＲＣss

– 30% of CRC feel busy、30% feels difficult to continue.–– 60% of the institutions request full60% of the institutions request full--time recruited time recruited CRCsCRCs. . –– More than 30% of the institutions in need of More than 30% of the institutions in need of CRCsCRCs..– CRCs feels difficult in handling adverse events, intersectional coordination, regulation and

bio-statistics.•• IRBIRB MembersMembers

– Difficult in appointing members who are knowledgeable about trials.– Less opportunity of training.– Non-medical members do not express their opinions frequently and feely.

•• Data managersData managers– 50% of DMs have Medical-related qualifications. – Main duties: clinical research, but less clinical trials– No established training system.

•• 30% of the institution feel in need of supporting secretary staf30% of the institution feel in need of supporting secretary stafff

Status surveillance report: Human resourcesStatus surveillance report: Human resources346 institutions、1,620MDs、2,459CRCs、826 IRB Members

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Status surveillance report: clinical trial promotion/enlightenment189 ex-subjects、300 patients、824 non-patients人 total 1311

•• Participation triggerParticipation trigger– General information by mass-media, internet– MDs and CRCs directly triggered participation– Majority wanted to be explained by MDs and CRCs when enrolled.

•• Information access opportunityInformation access opportunity– More than 70% need more trial general information– “target disease”, ”name of drug under trial” are most wanted

information•• Satisfaction of participationSatisfaction of participation

– Contribution to new drug development– Face to face communication with CRCs– More than half of ex-subject willing to participate in trials.

•• Request when participate in trialsRequest when participate in trials– Prior information and follow-up information, including compensation.– Access to information on the outcome of the trial and launch

•• Disadvantage of trialsDisadvantage of trials– Fear for safety and efficacy– Fear for discontinuation of investigational drug after trial completion.

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Status surveillance report: procedure, format and ITStatus surveillance report: procedure, format and IT346 institutions answered

•• Clinical trial administrative windowClinical trial administrative window– Expert administrative section for clinical trials 71.4%– Unique administration window for sponsors 94.2%– More than 50% institutions allow postal procedure

•• Information provision opportunity wanted by sponsor Information provision opportunity wanted by sponsor – The majority provide past trial experiences– “target disease”, ”name of drug under trial” information is not sufficiently provided

by 30% of the institution.•• Administrative role sharing between sponsor and institutionAdministrative role sharing between sponsor and institution

– The many documents supposed to be made by institutions are formed by sponsor.

– 34.4% institutions request sponsor to participate in IRB to explain.

•• ContractContract– Over fiscal year contract or yield based payment: 76%– No refund 13.9%– National hospital contract format applied 30.6%, original format 39%

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Vertical Clinical Trial Networking (concept)Vertical Clinical Trial Networking (concept)

Unmet needs drug and devicesUnmet needs drug and devices Smooth subject enrollment and efficient clinical trial performance

Response to social needs Response to social needs

Capacity of institution

Time consuming subject entry

Rapid entry and accumulation

accelerate

○ Synergetic approach between CCRCs and MCTCs.

○ Knowledge and technology basis for specialized trials

○ Efficient human resource mobilization and staff training using the network

薬事承認へ

MCTC

MCTC

MCTC

MCTC

MCTC

MCTC

MCTC

MCTC

CCRC

Based on the networking, additional and intensive Based on the networking, additional and intensive capacity building for CCRC, MCTCcapacity building for CCRC, MCTC

Core Clinical Research Center (CCRC)

○ Field specific core hospital

○ Regional core hospital etc.

Major Clinical Trial Center (MCTC)

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CCRCs are expected to

• capable to plan and conduct investigator-oriented clinical research,

• capable to provide staff training (particularly for MDs)

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②教育研究機関

１案件 1000～3000万円程度

①臨床研究機関

１施設あたり 8,000万～1億円程度

参 加

臨床研究基盤整備推進研究

①医療機関毎に「臨床研究実施体制

整備3ヶ年計画」を策定

②院内人材（若手医師、看護師、薬剤師、生物統計学者 等）の育成・確保

③倫理委員会の教育・充実

④データ管理体制の整備

⑤臨床研究の企画・実施・評価

⑥関連施設の教育 等

課題の抽出など

目標 世界水準の臨床研究基盤の整備・国民に提供する医療の質の向上（EBMの実践）・新規治療法、新規医薬品・医療機器の開発促進（治験環境の整備）

実施形態：公募型

教育、アドバイス

①臨床研究教育プログラムの開発

②臨床研究教育の実施

（対象；医療従事者、倫理委員会等）

③臨床研究プロトコール作成支援

④臨床研究教育担当者の育成

⑤データ管理支援 等

採択施設 ・慶應義塾大学医学部

・独立行政法人国立病院機構本部

・国立成育医療センター

・国立がんセンター中央病院

・国立循環器病センター

採択施設 ・京都大学大学院医科学研究科

・国立がんセンターがん予防・検診研究センター

・滋賀医科大学医学部

・北里大学薬学部

シーズの発見

シーズの選別・組合せ 臨床研究非臨床

応用研究基礎研究

革新的な医薬品・医療機器等の実用化

（平成19年度）医薬品・医療機器等の研究開発事業

【創薬基盤総合研究】

＜医薬品分野＞ ○基礎研究成果の

臨床応用推進研究

【医療技術実用化総合研究】○臨床研究基盤整備推進研究○治験推進研究○臨床試験推進研究【新】

○ヒトゲノムテーラーメード研究

【医療機器開発推進研究】

＜医療機器分野＞

（括弧内 18年度予算額）

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これまで指摘されている治験活性化の課題（案）これまで指摘されている治験活性化の課題（案）

患者 普及啓発・ 患者への治験に関する情報提供手段の拡充・ 患者の治験参加へのインセンティヴ

受診・同意 治療・説明

医療機関

拠点 拠点 拠点

中核

体制整備・ 治験の中核、拠点となる医療病院の体制確保・ 医療機関間の連携と支援体制の確保

人材対策・ 医師の治験実施へのインセンティヴ・ ＣＲＣの実働確保・ 生物統計家、データマネージャーの確保・ ＩＲＢ委員等及び治験関連職員の教育・養成

効率化対策（１）

・ 電子データの利用・ 契約様式、ＣＲＦの統一化・ 治験契約窓口の一元化

効率化対策（２）

・ 電子データのインターフェース標準化（CDISＣ等）

医療機関と依頼企業との業務分担の明確化

モニターリング効率の改善へオーバークオリティの解消へ

製薬企業・ＣＲＯ

製薬企業・ＣＲＯ

製薬企業・ＣＲＯ

データ提出

依頼・モニター

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医薬品産業の国際競争力強化に向けて

医薬品産業の国際競争力強化について、政府全体として取組を進めている。

第１．国際競争力の強化１．我が国の国際競争力の強化（７）医薬・医療機器産業の国際競争力の強化がん等の生活習慣病や感染症等各種疾病対策の推進等国民の保健医療水準の向上に資する医薬

品・医療機器産業について、関係府省・機関、企業等の双方向の連携の下、特に基礎・基盤研究、臨床研究及び基礎研究から臨床研究への橋渡し研究を推進するとともに、臨床研究基盤の整備、治験環境の充実等の国民に医薬品・医療機器を迅速に届けるための環境整備を行う。また、後発医薬品の安定供給や情報提供の充実を図り、後発医薬品市場の育成を図る。これらの実現に向けて、官民対話を積極的に行うとともに、２００６年度中にアクションプログラムの策定を行う。

経済成長戦略大綱（抄）（平成１８年７月６日 財政・経済一体改革会議決定）

第２章 成長力・競争力を強化する取組１．経済成長戦略大綱の推進による成長力の強化（１）国際競争力の強化①我が国の国際競争力の強化・ 医薬品・医療機器産業の国際競争力の強化のため、治験環境の充実等を推進するとともに、２００６年度中にアクションプログラムを策定する。

第４章 安全・安心の確保と柔軟で多様な社会の実現１．社会保障制度の総合的改革・ 「健康フロンティア戦略」やライフサイエンス研究の一層の推進を図る。「がん対策基本法」に基づき、がん対策推進基本計画を作成し、がんの予防と早期発見、緩和ケアの推進、専門医党の養成、医療の均てん化、研究等を推進する。また、医薬品・医療機器の承認審査の迅速化、市販後安全対策の充実、後発医薬品市場の育成を図る。

経済財政運営と構造改革に関する基本方針２００６（抄）（平成１８年７月７日 閣議決定）

29

Medical Device MarketMedical Device Market

51(43%)

31(26%)21(18%)

17(14%)

68(43%)

42(26%)23(15%)

26(17%)

97(43%)

69(30%)

25(11%)

38(16%)

189(45%)

112(27%)

39(9%)

80(19%)

0

100

200

300

400

500

95 99 03 25（予測）

米国 欧州 日本 その他

１２０

１６０

２３０

４１９

世界市場（‘２５／’０３）：１．８倍

B$/年

出典：COCJ 重点技術産業競争力委員会、 原典：HIMA，Eucomed

30

Characters of Medical DevicesCharacters of Medical Devices

• Industry scale is small （1/5 of drug industry）• R&D expenditure ratio is low（1/２ of drug industry）• High risk devices depend on foreign developemnt• Foreign device manufacturers are not generally positive

to conduct clinical trialsWhile Japanese competitive companies have technology to develop high risk devices, they are not willing to develop such devices; fear of compensation, disgracing brand image

31

Challenges of medical device clinical trials

• Role of medical device innovation is expected in advanced therapy.

• Types of devices subject to clinical trials are limited, such as advanced devices.

• The statistical evaluation methods are under development.

• Clinical evaluation may not be necessarily done solely by clinical trials, may be done with clinical research. （GHTF）

• Capacity building is necessary for competent institution to conduct “clinical research”, before clinical trials. The institution may have to involve more for the development process than for drug.

• Regulatory hurdles for device clinical trial may have to be tailored, based on the diverse technology bases of devices

32

Scheduling for next action planClinical Trial Promotion 3 yearlyClinical Trial Promotion 3 yearly Action PlanAction Plan （2003-2005 FY） extension

Study Committee Surveillance WGs：

現在開催中 （平成１８年６月～）

Regulatory study committee

次期全国治験活性化５カ年計画作成のための検討

Target Implementation April 2007

Next clinical trial promotion action plan