Coronary Stent Innovation: Biological Poolability East and West ~PMDA View~ Mami Ho, M.D., Ph.D. Office of Medical Devices I, PMDA, Japan Firstly, we would like to express our appreciation, having an opportunity for this presentation. My name is Mami Ho, deputy director of Office of Medical Devices 1st, PMDA. Today, we would like to talk about a subject titled “Coronary Stent Innovation:Biological Poolability East and West”.

I have no real or apparent conflicts of interest to report. Mami Ho, M.D., Ph.D I have no real or apparent conflicts of interest to report.

Overview Problems of coronary intervention Review Point Points of concern in review process –non clinical part Clinical evaluation Points of concern in review process –Clinical part Summary This slide shows overview about today’ presentation ; 1.Problems of remained coronary intervention 2.Review point 3.Points of concern in review process –non clinical part 4.Clinical evaluation 5.Points of concern in review process –Clinical part 6.Summary

Problems of coronary intervention with DES Difficulty of treatment for Stent restenosis Required long dual antiplatelet therapy Late stent thrombosis As you know , we could take a paradigm shift about percutaneous coronary intervention by using drug eluting stents. But there are still remained these problems. 1) Difficulty of treatment for Stent restenosis 2)Required long dual antiplatelet therapy 3) Late stent thrombosis DES→BMSに比べて明らかな再狭窄抑制効果を示し、冠動脈血管内治療における標準療法としての地位を確立 残された問題点 ・未だ残るステント内再狭窄 ・長期間のDAPT ・遅発性ステント血栓症

What is the purpose of development? Review point What is the purpose of development? What is expected in utilization of additional materials? What character/performance was expected in the design for the behavior of additional materials? What are the appropriate evaluation that additional material could achieve the purpose? In our pre-marketing review process, these items should be clarified; What is the purpose of development? And what kind of materials is utilized to achieve the concept? What character/performance are expected in the design for the behavior of additional materials? What are the appropriate evaluation that additional material could achieve the purpose?  

Points of concern in review process non clinical part for innovative stent Characterization of Novel products Efficacy mechanism Safety Biocompatibility Behavior/profile in coronary artery (implantation, intermediate change, long-term) General requirements for stent products See/Refer the MHLW notification regarding stent products In this slide, we would like to briefly introduce the point to consider in non-clinical data review for innovative stent. Especially innovative stent needs to be clarified in following points; The additional characteristics of novel products. The mechanism of its efficacy Biocompatibility Behavior/profile in coronary artery Basically, it is important to confirm the stent satisfy the prerequisite of conventional coronary stents. When you develop coronary stent in Japan, please refer to a MHLW notification regarding stent products.

Other related requirements Materials for device stability and durability Materials for biocompatibility Evaluation using animal model Implant test in swine (pig) coronary arteries Nonclinical evaluation to determine if the device accomplish its purpose of development Off course following items that are general requirements for medical devices are required for coronary stent too: Device stability and durability, biocompatibility, and performance evaluation in animal study. And device concept validation by bench testing.

Review points –clinical evaluation What is clinical positioning of innovative coronary stent? DES Equal (+probable benefit?) Complimentarily? Completely different ? BMS Next, we briefly introduce point to consider in clinical review of innovative stent. Innovative stent needs to be clarified its clinical positioning/FEATURE/CHARACTER?. Should it be used as a conventional DES or BMS? Should it be used with a conventional device complimentaly? Should it be use compassionatively? CABG Balloon angioplasty

Points of concern in review process –clinical part Purpose of the clinical trial determine nonpriority to pre-existint DES? Subject patients similar population to pre-existing DES trials? Control arm comparison with DES arm may be applicable at present, with DES population as subject? Primary endpoints Clinical endpoints (e.g. TVF) ? The clinical positioning of the innovative stent could be clarified, we could be scientifically justified, objective of the study, study population, control arm, primary endpoints in clinical trial. When you compare the stent to existing DES, the study should be designed to make this comparison possible.

Points of concern in review process –clinical part Important items Duration of antiplatelet therapy? How to establish approvable timeframe? Necessary secondary endpoints? Items to be observed? Additional topics, e.g. facility of retreatment Long term outcomes Innovative stent might have undetected risk, so we should evaluate its clinical benefit. So following items are important in the review of clinical trial; The duration of antiplatelet therapy and its justification Secondary endpoints Clinical items to be observed Facility in case of retreatment Long term outcomes The necessity of innovative device development is understandable. The device may be an option to solve various remaining problems in existing stents. On the other hand, its clinical efficacy and safety are not yet to be clarified in many aspects, because of its state-of-the-art technology.

Review point What is the purpose of development Clinical positioning Risk Benefit Clinical positioning Alternative? or Unmet need? Various? or Brand new? Non-clinical test Clinical trial Purpose Study population Control endpoint Safety duration Nobel materials Efficacy Safety Device performance Appropriate study design and evaluation based on its clinical positioning Appropriate evaluation based on its concept As a summary, it is necessary to make clear what is the purpose of development. Should it increase the benefit or decrease the risk? If it would be clear , we could understand its clinical positioning. Regarding its clinical positioning, we could make clear patients population, suitable control, efficacy and safety measures. Off course, pre-clinical test and bench test are required.

Make clear the purpose or concept of the innovative stent Take Home message Make clear the purpose or concept of the innovative stent Then we could make clear its clinical positioning and the purpose of clinical trial Take Home message is Make clear the purpose or concept of the innovative stent Then we could make clear its clinical positioning/FEATURE/CHARACTER and the purpose of clinical trial

Handling of clinical study data on medical devices which was carried out in foreign countries (Notification by Director, Office of Medical Device Evaluation, Yakusyokuki-hatsu #0331006, March 31, 2006) 　　　　 http://www.pmda.go.jp/english/services/reviews/file/0331006No.pdf Clinical Data acceptable Corresponding country or region has its official legal regulation for performing clinical investigation of medical devices, and Such regulation is considered to be equivalent to or exceed the Japanese GCP regulation, and the data were obtained according to such regulation, or The data of investigation considered to be equivalent to the above. This slide shows the notification by MHLW about Handling of clinical study data on medical devices which was carried out in foreign countries. You can see this notification via PMDA’s homepage.

PMDA’s Consultation Menu Very early stage Non-Clinical CT required? CT Pre-application Market and Literature Surveys Stability Test Biological Safety Test Performance Test Exploratory Clinical Test Clinical Test for Verification Development of Application Dossier Electrical Safety Test Pre-development consultation Safety Confirmation Consultation Consultation on Clinical Evaluation Clinical Trial Consultation Pre-application　Consultation And this slide shows PMDA’s consultation menu. From very early stage to pre-application stage, we have offered various menu. [click] And these are new categories of consultations, prior assessment consultation and pharmaceutical affairs consultation on R&D strategy. Quality Consultation Consultation on Performance Test Exploratory Clinical Trial Consultation Application Procedural Consultation Pharmaceutical Affairs Consultation on R&D Strategy Prior Assessment Consultation

PMDA, Japan Mami Ho, M.D., Ph.D Deputy Review Director, Office of Medical Device I ho-mami@pmda.go.jp For more information, see our website: URL : http://www.pmda.go.jp/ PMDA/we suggest consultation meetings in an early stage of development for clinical trial designing. You can find that information via PMDA’s web site and it’ll also be welcomed to email me. Thank you so much for your kind attention!   Thank you! 15

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PMDA, Japan PMDA will keep our effort to continue valuable communication with FDA and the Industry through HBD activities and the Collaborative Review Scheme project. Thanks for your understanding and corporation. PMDAは日本における医薬品・医療機器の承認審査を行う機関です。医療機器のグローバルな開発・治験・承認を支援する一環として、米国FDAとの情報交換や、HBDでの産・学との協働、またコラボラティブスキームと呼んでいるFDAとの共同審査パイロットプロジェクトなどを行い、有効性・安全性が確認された医療機器を国民に提供するために努力しています。 これからもご協力のほどよろしくお願い申し上げます。 PMDA is a regulatory authority to review pharmaceutical medicines and medical devices in Japan. As a part of our activity to support global development of medical devices, we exchange information with FDA, collaborate with industry and academia through HBD, and conduct a pilot program called collaborative scheme with FDA. In that way, we keep making our effort to provide people with medical devices which has confirmed efficacy and safety. We hope to have your continuous cooperation to achieve our common goal. For more information, see our website: URL : http://www.pmda.go.jp/ 17

Review point 有効性を高める リスクを減らす 使用性能の向上 開発の目的は何か 治療選択肢を増やす 新しい治療法 Risk 治療選択肢を増やす 新しい治療法 治療ができない患者へ 治療提供 Benefit 臨床上の位置づけは 臨床上の位置づけに基づいた評価 非臨床 臨床試験 新規部分について -有効性のメカニズム -安全性 既存機器と同じ部分について -基本性能の担保 　　ｰ安全性 目的 対象 対照 主要評価項目（有効性） 安全性をどう評価するか 観察期間 臨床上の位置づけに基づいたデザインと評価 まとめますと、新しい冠動脈ステントの開発において、何を意図したものかを明確にする必要があります。既存治療の有効性を高めるものなのか、安全性上の問題を減らすためのものなのか。ユーザビリティをあげるものなのかなど。 この点が明確になれば、新しいステントが既存治療と同じ患者を対象として、有効性を高めるか、安全性を高めるか、あるいは今まで治療を受けられなかった患者に治療が提供できるものなのか、等が明確になります。 すると、臨床試験で、誰を対象に、何を対照として、どのような検証を行うべきかが明確になります。 もちろん、臨床試験に入る前に、非臨床試験にて、設計検証、安全性の検証を行う必要があります。

Action Program for Acceleration of Medical Device Reviews　(issued in Dec. 2008) MHLW / PMDA will accelerate the Medical　Device review processes and reduce total　review time* to approval, on the premise of ensuring quality, efficacy, and safety of medical devices paying due consideration to minimize burdens to applicants under combined efforts by both the regulatory side and the applicants side by taking scientific and reasonable measures In recent years, there were some problems of medical device review process including prolonged review time. In order to solve these problems, “Action program for acceleration of medical device review” has been issued on December 11th, 2008. It says that MHLW / PMDA will accelerate the Medical　Device review processes and reduce total　review time* to approval, on the premise of ensuring quality, efficacy, and safety of medical devices paying due consideration to minimize burdens to applicants under combined efforts by both the regulatory side and the applicants side by taking scientific and reasonable measures (* Total elapsed time from submission to approval)

Performance Goal & Annual Milestone of Action Program Full transition to Third-party Certificate of Class ⅡMDs Set review time goals Clarify review criteria Introduce 3-Track system Improve quality by increasing the number of staff and enhancing training FY2013 FY2012 FY2011 FY2010 FY2009 Design Training Program 3-track Review System Prepare the operation Increase staff　35 → 104 by FY2013 Formulate Approval standards/Good Review Guideline Generic(Me-too) MD (Kohatsu):　4 mos. Improved MD (Kairyo): w/ clinical data 10 mos. w/o clinical data 6 mos. Brand-New MD (Shin): Standard 14 mos. Priority 10 mos. Transit by FY2011 So, To achieve the purpose of the action program, performance goal and annual mile stones were set as shown in this slide. For example, increase of reviewers start from FY2009 and will end on FY2013. The number of reviewers will be increased gradually during FY 2009 to 2013. And We had prepared for the introduction of 3-track review system in FY2009 and 10, and then it was started operation in April 1st, 2011. And we set review time goals on each category of application, Bland-new devices, improved devices and generic devices. Review time goals are decreasing year by year.

http://www.pmda.go.jp/english/service/notifications.html ここからは、平成18年に発出された、海外で実施した臨床データの取扱いに関する通知ついて説明いたします。 この通知や関係文書については、PMDAのホームページで日本語版も英訳版も掲載されておりますので、詳細については別途ご確認いただければと思います。 内容について簡単にご説明しますと、まず、受け入れ可能な臨床試験としましては、 臨床試験が行われた国で、医療機器の臨床試験の実施基準が定められていて、その基準が日本のGCPと同等の基準であること、その基準に従って実施された臨床試験であること、 とされています。

Regulatory Focus 2010 (April), pp40-44 Comparing GCP Requirements for Medical Device Clinical Trials in the US and Japan (conducted by HBD WG4) WG4 subcommittee conducted a study comparing international GCPs. The objective was to determine if the differences identified were substantive with respect to four fundamental criteria pertinent to well-controlled clinical studies. • research subjects’ rights, safety and welfare • scientific integrity of the trial methods • data quality and integrity • reliability as a basis for regulatory decision making Regulatory Focus 2010 (April), pp40-44

Number of Medical Devices Approved with Clinical Data Review http://www.pmda.go.jp/english/service/faq2.html

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