Medical Device Evaluation Division, Using Post-Marketing Surveillance for Safety Measures - Japanese Regulatory View - Akihide Konishi Medical Device Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health, Labour and Welfare The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to MHLW/PMDA

  I, Akihide Konishi, 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.

Meanings of Post-Marketing Surveillance (Use-Results Survey, Re-examination) As the number of cases and the evaluation period are limited in premarket clinical trials, there is a possibility of encountering unknown adverse events after the device is introduced into the market. While the subject device is used in the limited number of medical institutions in clinical trials, many facilities will use the device in the actual clinical practice, therefore, the same results as those in the clinical trials may not be always obtained. The system has been established, where manufacturers are mandated to re-confirm effectiveness and safety of the device at certain point of time after approval, by collecting the actual use-results from medical institutions.

Under the new law revised on November 25, 2014, Re-examination System has been transformed into Use-Results Survey System. Re-examination System (under the previous law) 1. Re-examination was mandated for brand-new medical devices. 2. Re-examination period was uniform across the category*. *Category：Orphan MD : 7 years, MD with novel structure: 4 years, Other MD: 3 years Use-Results Survey System (under the current law) 1. Use-results survey, for the time period as necessary, is obligated for the devices for which survey is required*. 　2. Applicants may reasonably decide the evaluation period on their own judgments, as the system allows some flexibility. * Devices requiring survey: Mainly brand-new medical devices, that have no similar devices in or outside Japan, or those with which use experience is scarce.

Overall Process of Use-Results Survey Application for review of use-results Premarket application Pharmaceutical Affairs and Food Sanitation Council Start marketing Registration complete Preparation Registration Follow-up Regulatory review Use-Results Survey (GPSP compliant） Approval GPSP: Good Postmarket Surveillance Practice (Ordinance) Within 3 months after the completion of survey Annual report Report should be submitted annually from the date of marketing approval, within 2 months after the end of each reporting period, in principle. Submission of master surveillance plan

Absorb GT1 The scaffold is made of bio-absorbable polylactate, so that it will be decomposed and absorbed after physically maintaining lumen patency for the time period required for revascularization. The scaffold is coated with a cell proliferation inhibitor and a bio-absorbable polymer.

Clinical Trial Clinical trials in the US and in Japan have been conducted to demonstrate effectiveness and safety of the product, using the previous generation device (AVJ-301). Both trials were designed to confirm non-inferiority to XIENCE, and it was demonstrated that AVJ-301 cohort has no inferiority to XIENCE cohort in the primary endpoint of target lesion failure (TLF) at 12 months after procedure.

Clinical Trial Results in Japan (Stent Thrombosis Rate) Although no difference was observed in the stent thrombosis rate at 12 months after procedure, a tendency of higher thrombosis rate in AVJ-301 cohort has been observed at 24 months after procedure. Stent thrombosis rate AVJ-301 cohort XIENCE cohort 12 months after procedure 1.5% (4/262) (2/133) 24 months after procedure 3.1% (8/257) (2/130)

Cause Analysis of Higher Thrombosis Rate The biggest concern at the start of the clinical trial was the stent fracture caused by overexpansion, therefore, post-dilatation after diagnostic imaging was not recommended. Results of the post-analysis of the trial in Japan showed lower stent thrombosis rate in those cases where diagnostic imaging and post-dilatation after procedure were carried out appropriately, compared with those cases where these procedures were not taken appropriately. Appropriate diagnostic imaging and stent size selection, as well as proper post-dilatation are important factors, and that procedural effect might have resulted in higher stent thrombosis rate.

However, re-evaluation is needed to demonstrate that thrombosis rate can be reduced by the proper treatment after procedure, as described earlier. or Retrial Approval Rigorous data collection in post-market is mandated, with proper use of the device ensured in the selected facilities (mainly clinical trial facilities). It was decided that if it could be determined, based on these post-market data, that the stent thrombosis rate was lower than the predetermined criterion, then the user facilities would be increased.

Overview of Use-Results Survey and Post-Marketing Safety Measures 2,000 cases Qualified facilities* All case registration 3-month follow-up Use-Results Survey If stent thrombosis rate in 2,000 cases up to 3 months after placement exceeds 0.9 %, cause investigation and proper measures must be taken. * Those facilities qualified for clinical trials or approved by the relevant society Stent thrombosis rate in 2,000 cases up to 3 months after placement does not exceed 0.9 % Step by step expansion of facilities　 Marketing Phase 1 Stent thrombosis rate in 250 cases in the survey up to 2 years after placement does not exceed 1.5 % Facility expansion pace will be revised.　 Marketing Phase 2 2-year PMS results of stent thrombosis of 2,000 cases Re-evaluation of facility requirements

Conclusions Use-Results Survey is the system where effectiveness and safety of the device can be evaluated based on the actual use in the clinical practice. As explained using examples, safety of the device in the clinical practice can be re-confirmed, and the decision whether to expand user facilities can be made, by investigating the use-results survey data from the confined facilities in the post-market. Use-Results Survey is a valuable system for both medical device development and post-marketing safety measures. 学会と連携したレジストリー