Clinical Needs and Current Situations of Endovascular Treatment Devices for Pediatric Cardiology JP Academia HISASHI SUGIYAMA Japanese Society of Pediatric Cardiology and Cardiac Surgery Japanese Society of Pediatric Interventional Cardiology Pediatric Cardiology, Tokyo Women’s Medical University

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Grant/Research Support Consulting Fees/Honoraria Major Stock Shareholder/Equity Royalty Income Ownership/Founder Intellectual Property Rights Other Financial Benefit Company Names

Introduction The modern progress and smooth introduction of new devices for catheter intervention impacts on remarkable clinical improvement in adult cardiology, while those could make a slow step in pediatric cardiology. Time lag of the new device approval in pediatric cardiology is always a issue both in Japan , in USA, and in other countries. In Japan, such trends shows more evident as slow introduction of catheter devices to cath.lab, since it has been taken decades to approve Amplatzer septal occluder, duct occluder, Vascular plug, RF wire and Occlutech device. CP stent for pulmonary stenosis is now under investigator-initiated clinical trial.

CE mark PMDA FDA Conformity to CE mark Developed countries Developing countries Alternation for surgery Economical reason Safety efficacy cost-effectiveness

Un-approval device in Japan Category Availability Device 1 Approved & available world wide except Japan ・Large stent (new generation) ・ADO II, musc VSD occluder ・Melody V, Sapien V（TPVI） 2 Not approved but used as Off-label in US (and Japan)　 ・Melody for other valves ・Stent for PS ・Stent for PDA 3 Not approved in US and Japan 　（only CE mark） ・Venus P valve ・ADO-II AS ・Andra stent 4 Under developing 　（Human trial will be started） ・BVS for children ・Harmony valve

Occluder-1 Japan US Europe East Asia ASEAN （Korea, Taiwan） Amplatzer 〇 Septal occluder 〇 Cribriform PFO occluder ◯ Duct occluder Duct occluder II Duct occluder II AS MusVSD occ. Perimem VSD occ. Vascular Plug Vascular Plug II Vascular Plug III Vascular Plug IV

Occluder-2 Japan US Europe East Asia ASEAN （Korea, Taiwan） Occlutech Septal occ. Figulla Flex II 〇 Duct occluder VSD occluder LifeTech Septal occluder Vascular Plug Cocoon 〇(Korea)　 〇(Korea) pfm Nit-occlude Le VSD occluder

Percutaneous Pulmonary valve implantation Japan US Europe East Asia ASEAN （Korea, Taiwan） Medtronic Melody 〇 △ Edwards Sapien 〇HDE MedTech Venus P valve Clinical trial Harmony

Available but off-label Stent　 Japan US Europe East Asia ASEAN （Korea, Taiwan） Cordis Palmaz 〇 △ NuMed CP Clinical trial PMA for CoA 〇（Taiwan) Genesis Available but off-label 〇（Taiwan) 　 Andramed Andra Bard Vaｌeo OptiMed OptiMed PDA

Conducted by Dr. Hideshi Tomita 5/18/2018 8:22 PM Stent for Pediatric use has not been approved for decades because of difficult conduction of industry- initiated clinical trial due to economic reason (small market and vast efforts to get approval of administration. Investigator-Initiated Clinical Trial of CP stent for pulmonary stenosis in Japan Conducted by Dr. Hideshi Tomita Toshiki Kobayashi, Hitoshi Kato, Hisashi Sugiyama with coorperation of JPIC academy members © 2007 Microsoft Corporation. All rights reserved. Microsoft、Windows、Windows Vista、およびその他の製品名は、米国およびその他の国における登録商標または商標 です。 ここに示す情報は参照だけを目的とし、発表時点での Microsoft Corporation の見解を表します。 Microsoft は変化する市況に対応する必要があり、この発表は Microsoft のコミットメントとして解釈されるものではありません。また Microsoft はこの発表日以降に提供されるあらゆる情報について、その正確性を保証できるものではありません。 Microsoft はここに示される情報について、明示、黙示、または法令を問わず保証をしません。

Background Stenting for great vessel stenosis associated with congenital heart diseases has been established procedure Although some stent approved for CoA by CE mark, no stent officially approved for pulmonary stenosis, even in US and Europe Consequently, stenting for PS or CoA has been off-label, also in our country Despite negotiation between our society and PMDA for longer than 20 years, no stent has officially been approved for congenital heart diseases

Registration； 32patients Age；3-36（median 11) yo. 3-9yo；　　12 10-19yo； 13 20yo～；　 7 Weight；12-69（median38） kg 10-14kg； 2 15-19kg; 5 20-24kg; 2 25-29kg; 3 30kg ～; 30 Pathophysiology Bi-ventricular physiology 　　27 Single ventricular physiology 5 Indication 　　　 Pressure gradient 　6 　 Stenosis ratio 　　 22 　 RVSP 　　 　3 　 SpO2(Fontan)　 　 　1 　Completely stent implantaｔion；22 patients

CP stent was approved for CoA (COAST II), and will be approved for right ventricular outflow tract conduit by FDA. CP stent for pulmonary stenosis clinical trial will be completed in Japan by April 2017. Comprehensive approval of the CP stent (PS, CoA, RVOT and covered CP stent) will be expected in next year.

Research & development of new device Regulatory Ease regulation Simplified of clinical trial Adjusting regulation between US and Japan HBD for children Public grant Industry Academia Cost of approval process Physician oriented clinical trial Research & development of new device Market scale Enlighten and education Contribution to society Certification system