Using Real-World Evidence (RWE) Japanese Academia view Hiroyoshi Yokoi, MD. Fukuoka Sanno Hospital (Japan)

Disclosure Statement of Financial Interest I, (Hiroyoshi Yokoi) DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

What’s RWE 昨年よりRWEの報告がFDAやNEJMよりなされています。 FDA and NEJM has reported RWE since last year.

Definition (FDA draft guidance) Real-World Data (RWD) is data collected from sources outside of traditional clinical trials. These sources may include large simple trials, or pragmatic clinical trials, prospective observational or registry studies, retrospective database studies, case reports, administrative and healthcare claims, electronic health records, data obtained as part of a public health investigation or routine public health surveillance, and registries (e.g., device, procedural, or disease registries). The data is typically derived from electronic systems used in health care delivery, data contained within medical devices, and/or in tracking patient experience during care, including in home-use settings. Real-World Evidence (RWE) is the evidence derived from aggregation and analysis of RWD elements. RWEとは古典的な臨床試験とは異なり、レジストリー研究などから得られるRWDを集積し、分析して得られるエビデンスのことであります。 RWE is the evidence derived from aggregation and analysis of the data from registry types of studies, unlike the one based on the traditional clinical trials.

Clinical studies for device-development Schematic flowchart of device-development Submission Approval non-clinical studies Clinical trials (feasibility/Pivotal) PMS (post marketing surveillance) Industry-initiated clinical registries literature review Investigator-initiated clinical registries 承認前の臨床試験は承認を得るために有効性と安全性を評価します。市販後調査は実臨床での安全性を評価します。その後、企業主導または医師主導で行われる臨床試験は実臨床での有効性と安全性を評価します。 In the pre-approval clinical trials the efficacy and safety of the investigational drug/devices are assessed. And post marketing surveillance involves the safety assessments in the real-world clinical practice. And then, Industry-Initiated or investigator-initiated clinical trials are conducted and further efficacy and safety of approved devices are assessed in a “real world” clinical setting. safety and efficacy data for regulatory approval focused on safety data in real world practice safety and efficacy data in real world practice

Pivotal study for regulatory application Pros. controlled high level evidence Cons. limited population high cost “real world data” is help to understand the medical front activities Kravitz RL et al, Milbank Q. 2:661-87, 2004 承認を取得するためのPivotal Studyはよくコトールされており、高いエビデンスレベルを有しますが、限定した集団であり、費用もかかります。一方で、RWD は医療の最前線を理解するの助けになります。 A pivotal study is generally well-designed and well-controlled to obtain approval for investigational drug/device with high-level evidence. However, the study subject population is more limited and it costs a lot for organization the study. On the other hand, RWD will help us to understand 'real world' frontline experiences .

Utilization of Real World data Real world data is useful to understand safety and efficacy under real-world practice Sources Registries Large Simple Trials observed cohorts of patients with diseased or treatment observed trials with large populations but less cohorts than RCT Supplement of RCTs Retrospective database studies RWDは実臨床における有効性と安全性を評価します。データーソースとしてはレジストリー、RCT, 大規模な観察研究、後ろ向きレジストリー研究が含まれます。 RWD is used for assessing efficacy and safety of drugs/devices in real-world clinical practice. Data sources include registries, RCTs, large observational trials, and retrospective registry studies. supplement data from RCT retrospective analysis to utilize medical database Medical records Others review of medical charts of patients

Experience in Japan Government originated Academia originated J-MACS Academia originated Olive registry J-PCI registry Industry originated Zilver-PTX Japanese PMS 日本の最近のRWEの経験を紹介します。政府主導でJ-MACS、医師主導でOliveレジストリー、J-PCIレジストリー、企業主導でZilver-PTX市販後調査があります。 I’d like to introduce some recent experiences of RWE in Japan. We have government-initiated study, J-MACS. Investigator-initiated studies, Olive registry and J-PCI. And industry sponsored study, Zilver-PTX PMS.

J-MACS Project to collect post-marketing data for ventricular assist device (VAD) in Japan ALL patients cooperation between Industry, government and academia harmonized with US program (Inter-MACS) through HBD J-MACSは左室補助デバイスの前向きレジストリー研究で前例登録となっています。産官学の協力でこのレジストリーが行われています。 HBDを通じて米国のプログラムと国際協調をしています。 J-MACS is a prospective registry study of left ventricular assist device. In this study all implanted patients are to be registered. The registry study has been conducted under the collaboration between industry-academic and government. The study has got involved with the US program from the international cooperation perspective through HBD (Harmonization By Doing),

J-PCI registry J-PCIは本邦における心血管インターベンションの前向きレジストリー研究で、CVITが行なっています。 J-PCI is a prospective registry study of Cardiovascular Intervention in Japan, and has been conducted by the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT).

J-PCI registry initiated by CVIT (Japanese Association of Cardiovascular Intervention and Therapeutics) ２０１１年には18万件のPCIの初期データーが登録されており、現在は20万件以上の症例が登録されており、本邦のPCIの80%が登録されています。 The initial PCI data of one hundred eighty thousand was registered in 201. Subsequently, more than two hundred thousand data has currently been registered and about 80% of Japanese PCI cases have been registered in total.

Olieveレジストリーは本邦におけるCLI患者に対するBTKに対するEVT後の予後を前向きに調査した、医師主導の臨床研究です。 Olive registry is an prospective investigator-oriented clinical study to assess the clinical outcomes after endovascular therapy ( EVT ) for BTK lesions in CLI patients in Japan.

PPは切断を回避する生存率、二次評価項目として初期成功率、周術期合併症としています。 Primary endpoint is amputation free survival rate. Secondary endpoints are early successful outcome rate and perioperative complication rate.

３１２例の患者が登録され、２１３例が下肢切断を回避して生存していました。 A total of 312 patients was registered. Of these patients, 213 patients have survived without lower limb amputation.

患者背景では高齢者、糖尿病患者が高率で、約半数が透析患者でした。 Baseline characteristics shows a high percentage of elderly or diabetes mellitus patients and approximately half of patients receive dialysis.

１２ヶ月目のAFSは７４％、MALE回避率は８８％で米国のOPGをクリアしていました。 AFS at 12 months was 74% with MALE free at 12 months being 88%, which met the US objective performance goal (OPG) .

Zilver PTX Japan PMS H Yokoi, LINC2016

Japan PMS Compared to RCT and SAS H Yokoi, LINC2016

Patient Demographics and Comorbidities H Yokoi, LINC2016

Baseline Lesion Characteristics H Yokoi, LINC2016

Baseline Clinical Assessment H Yokoi, LINC2016

24-month Follow-up for Japan PMS 907 patients and 1075 lesions treated with 1861 Zilver PTX stents 721 patients eligible for 24-month follow-up 85 deaths, 66 lost to follow-up, 27 withdrew, 8 not yet due 24-month follow-up currently available for 624 patients 86.5% follow-up compliance Patency assessed by ultrasound at sites where this was standard of care No significant differences in demographics, comorbidities, or lesion characteristics compared to patients who did not undergo ultrasound

Thrombosis/occlusion H Yokoi, LINC2016

Freedom from TLR H Yokoi, LINC2016

Clinical Benefit H Yokoi, LINC2016

Learned from Japanese studies OLIVE registry first registry to collect peripheral interventional real-world data in Japan good evidence to understand real medical situation, and help to consider medical guidance Zilver-PTX Japanese PMS post- marketing surveillance for Zilver-PTX (DES for peripheral arteries) first evidence of real-world data in Japan, and help to set-up medical practice

Conclusion pre-marketing data (mainly RCT data) is well-controlled, but limited information in limited population Registry studies are useful to understand safety and efficacy under real-world practice It’s important to establish well-working system by cooperation between Industry, government and academia, and between US and Japan

Thank you for your attention!