DEVELOPMENT PROCESS OF HIGH-LEVEL MEDICAL PRODUCT

Transcription

1 EMERGING TECHNOLOGY AND REGULATIONS OF MEDICAL DEVEICE IN ASIA-PACIFIC REGION October 29-30, 2013 IN TAIPEI DEVELOPMENT PROCESS OF HIGH-LEVEL MEDICAL PRODUCT IN JAPAN TAKING THE CORONARY STENT CASE October 30 th, 2013 Mime Egami Chief Representative, RAPS Japan Visiting Professor Chief Medical Innovation Officer Tokyo Women s Medical University

2 Tokyo Women s Medical University Waseda University Joint Institution for Advanced Biomedical Sciences (TWIns) TWMU Area Center for Advances Biomedical Sciences Cell Processing Center (GMP leve), Experimental Room for Cell/ Molecular Biology, Polymer Chemistry & Biomedical Engineering. Advanced Robotic Surgery Room with open MRI/CT (Intelligent Operating System) for advanced device develop. Medical Innovation Laboratory Collaboration area for companies, & RAPS Japan TWIns 22,000m 2 Waseda Area Center for Advanced Biomedical Sciences Fusion Area Researchers of both univ to learn and debate. TWMU runs 1yr BMC since 1968 with 1,700 ind.graduaes, Biomedical PhD course since 2000, and Regulatory Science joint PhD course since 培養室 Cell Processing Center(GMP) Intelligent Operating System (Open MRI & large animal CT) Integrated Surgery Room 医学と工学の融合を促進する for Alternative MD Experiments 2 アメニティエリア

3 Daily Practice of Biomedical Engineering at TWIns BME Student Industry Technician AD MD MD MD Scientists, Physicians, Industry Experts make one unified team for clearly visualized goal, sharing different logics & approaches for creation of innovative therapy 3

4 DEVELOPMENT PROCESS OF HIGH-LEVEL MEDICAL PRODUCT IN JAPAN < First Part > 1. Overview of approval application for medical devices 2. Outline of Case study (drug-eluting stent) < Second Part Case Introduction > 3. Process BEFORE submission: development of regulatory application strategy 4. Process AFTER submission: new/improved medical device with clinical data 5. Approval Application Form 6. Approval Conditions, Use-Results survey & PMS < Third Part RAPS Japan activity > Self disciplinary educational efforts by RAPS Japan volunteer members 4

5 OVERVIEW OF APPROVAL APPLICATION FOR MEDICAL DEVICES 5

6 Japan Medical Device Regulations Trend & Development Regulatory categories in Japan Pharmaceutical Affairs Law (PAL) for Product Medical Practitioner s Act Medical (Care) Act for Treatment 6

7 PROCESS FROM DESIGN DEVELOPMENT INTO MARKETING APPLICATION Pre-marketing Approval Review Quality Management System Source: Waterfall model for design control Intended use Customer needs Design Development Design inputs Essential Principles, certification/approval standards, information on similar devices, and risk analysis Design process Verification Design outputs Conform to input requirements Validation Medical device Manufacture Process validation Postmarketing 7

8 Regulatory Process for Medical Devices: By Risk Classifications [Products (Medical Devices)] [Procedure] [Authorized person Manufacturing & Selling Utilities or institution] Highly Controlled Medical Devices*1 Class Ⅳ Class Ⅲ Class Ⅱ Controlled Medical Devices 2 Class Ⅱ General Medical Devices Class Ⅰ Application for Approval Application for Certification Notification Minister of MHLW (PMDA) 1 Controlled Medical Devices except Controlled medical devices certified by Ministry of MHLW Accredited Certification Utility (non-government) 2 Controlled medical devices certified by Ministry of MHLW Minister of MHLW (PMDA ) 8

9 Approval Review Category For the purpose of the approval review, medical devices are divided into the following 3 categories apart from Classification. This per-category review has been in effect since Review category Description New medical devices etc. Improved medical devices Generic medical devices Medical device of which structure, usage method, indications, effects or performance is clearly different from those of medical devices already approved (Clinical trials are required as a general rule.) Medical device which is not innovative enough to be subject to the reexamination, but of which structure, usage method, indications, effects or performance is not substantially equivalent to those of medical devices already approved (Clinical trials may be required.) Medical device of which structure, usage method, indications, effects and performance are substantially equivalent to those of medical devices already approved (Clinical trials are not required.) 9

10 Listing of Data Required for Approval Application for Each Review Category a. b. c. d. e. f. g. h. Application category Development Specifications Stability Conformity to standards Performance Risk analysis Manufacturing Clinical evidence New medical devices etc. Improved medical devices Generic medical devices Class IV, Class III or II Class IV, Class III or II (With clinical data) Class IV, Class III or II (Without approval standards, without clinical data) Class IV, Class III or II (Without approval standards, without clinical data) Class IV, Class III or II (Without approval standards, without clinical data) Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ Δ : denotes that the data must be submitted. : denotes that the data need not be submitted. Δ: denotes that the data to be submitted is determined on a per-product basis. For the numbers 1 to 3 in the columns a. to h., refer to the numbers in the Contents of submitted data column on the following slide. 10

11 MAJOR PROCESS FROM BASIC STUDY TO POST MARKETING Basic Research Preclinical Clinical Trial Clinical Study Application for Approval Revi ew Approval Post Approval Basic Designing No Clinical Trial Proto Design Improvement Various tests by reflecting product specificity Biosafety, Standard, QMS, Stability, Electricity Safety, Mechanical Safety etc. No human study required if other data available to judge safety and efficacy Yes Clinical Trial If no serious gap between races such as metabolism, foreign clinical trial data can be inserted Documents for Application Clinical Trial to Perform Small size ( Evaluation of usage or protocol ) Large size ( Total evaluation of safety and efficacy ) Approval Review by PMDA Approval by Minister MHLW PMS Survey and Other Data collection for proper usage Reference: MHLW presentation at JMDA seminar 11 11

12 RELATIONSHIP BETWEEN DESIGN DEVELOPMENT AND MARKETING APPLICATION DOSSIERS Source: Waterfall model for design control Pre-marketing Approval Review Quality Management System Intended use Customer needs Essential Principles and conformity Overseas usage conditions After verification Rationale for product specifications Design inputs Essential Principles, certification/approval standards, information on similar devices, and risk analysis Verification Design process Summary of design verification Design Development Design outputs Conform to input requirements Compliance inspection Risk リスク分析 analysis Entry to approval certificate Shape/Structure column Raw Materials column Product Specifications column Manufacturing Method etc. Manufacturing information Validation Reliability 信頼性調査 assessment Summary of validation (performance/clinical study) Approval application form Device description Labeling Medical device Manufacture Process validation 12 Postmarketing *Written in red: STED items

13 Image of Approval Application Dossiers Essential Principles conformity checklist Medical device approval application form [1] Category [2] Name (generic name and brand name) [3] Intended Use and Indications [4] Shape, Structure, and Principle [5] Raw Materials or Components [6] Product Specifications [7] Operation or Usage Method [8] Manufacturing Method [9] Storage Method and Expiration Period [10] Manufacturing Site of Marketed Product [11] Manufacturing Site of Raw Materials [12] Remarks Instructions for use (draft) etc. Summary Technical Documentation (STED) Summary of product Essential Principles and Conformity Device Description Summary of Design Verification and Validation Labeling (draft) Risk Analysis Manufacturing Information Submitted data a. Origin or history of discovery and usage conditions in foreign countries, etc. b. Setting of specifications d. Conformity to the standards stipulated in Article 41, Paragraph 3 of the Pharmaceutical Affairs Law Zzzz c. Stability and durability e. Performance f. Risk analysis g. Manufacturing method h. Clinical evidence 13

14 2. Case Study of NOBORI ( drug-eluting stent: the drug part is not discussed at this session ) 14 Overview of product History of development Stent assessments Delivery catheter assessments Clinical study design

15 CASE STUDY DRUG-ELUTING CORONARY STENT Product overview: Class IV medical device Intended to be used in patients with coronary obstruction or stenosis to ensure blood flow in the blocked or narrowed segment (lesion) and maintain the patency. A supporting structure, which expands and remains inside the coronary vessel, delivered to the lesion by the balloon catheter. The stent remains in place after the catheter is removed. Primarily made of metals. Any immunosuppressive drug is applied to locally inhibit neointimal proliferation in the tissue. 15

16 DRUG-ELUTING STENT IS MEDICAL DEVICE IN JAPAN The primary mode of action is to widen a narrowed coronary artery, and the drug is used to prevent in-stent restenosis after neointimal proliferation following stent placement. Therefore, a drug-eluting stent including NOBORI reviewed as Medical Device, not DRUG. then, you may properly breakdown each characteristics of the product 16

17 THERAPEUTIC MODALITIES (CHOICES) FOR CORONARY ARTERY STENOSIS 1) Pharmacological therapy 2) Surgery Coronary artery bypass (aorto-coronary [AC] bypass grafting) 3) Percutaneous trans-luminal coronary angioplasty (PTCA) PTCA balloon Stent: bare metal stent and drug-eluting stent Rotablator 17

18 PRODUCT COMPONENT (AND REPRESENTATIVE INPUT INFORMATION) Stent body: Is placed in the coronary artery (permanent placement, effect of heartbeats, non-biodegradable etc.) Exerts expansive force to keep the inner diameter of the stented segment Delivery system: Delivers the stent to a segment to be placed Expands the stent to an appropriate diameter in the stented segment (Eluting drug): Prevents new tissues from excessively growing into the stent lumen 18

19 PROCESS BEFORE SUBMISSION: DEVELOPMENT OF REGULATORY APPLICATION STRATEGY 19

20 Classification and Application Category of Medical Devices General medical devices Class I Controlled medical devices Class II Specially controlled medical devices ClassIII/IV Not into category of new medical devices Certification standards established and designated by the ministerial notification? Approval standards established and met within the scope? Differential from the approved product shows no substantial difference in the efficacy or safety Marketing notification <PMDA> Marketing certification application 20 Third party certification body Marketing approval application Approval standards established Marketing approval application Generic medical device NO YES Differential can be verified by methods other than clinical trials Has highly innovative indication(s) or structure NOBORI Marketing approval application Improved medical device without clinical data Marketing approval application Improved medical device with clinical data Marketing approval application New medical device PMDA

21 ARE CLINICAL STUDY DATA REQUIRED? The clinical efficacy and safety cannot be evaluated only by results from nonclinical testing such as performance testing and animal testing. Falls into the category of medical devices of which performance, structure, etc. are clearly different from those of already approved medical devices (new medical device). Clinical data required Can be evaluated by existing literature etc.? No Clinical trial required Japanese? Overseas? Yes Collect evaluable literature and prepare a clinical evaluation report. Japanese clinical trials are required if only overseas data are available and they are difficult to extrapolate to Japanese patients. To determine the necessity, PMDA s clinical evaluation consultation or preapplication consultation has to be utilized to set proper strategy mutually agreed! Refer to PFSB/ELD/OMDE (Yakushokuki) Notification No , August 4,

22 CAN DATA OF CLINICAL STUDY CONDUCTED IN FOREIGN COUNTRIES BE USED? Requirements for acceptable overseas data The clinical study must have been conducted in a country or region where GCP principles equivalent to or better than Japanese GCP are established, in accordance with that GCP principles. Documents equivalent to or better than essential documents laid down in GCP have to be prepared. The sponsor of the clinical study and trial sites have to be ready for cooperation in post-submission reliability assessment (on- or off-site). Applicants have to ensure reliability of the entire clinical study by audit or other means. Documents should be retained so that after approval application, quality assessment (on- or off-site) can be conducted similarly to Japanese clinical studies. For clinical studies reviewed/approved in any other country, inspection with emphasis on process rather than documents is conducted. Documents equivalent to GCP essential documents need to be obtained before submission! 22 For details, see PFSB/ELD/OMDE (Yakushokuki) Notification No , March 31, 2006 and Q&A.

23 FALL INTO CATEGORY OF NEW MEDICAL DEVICES? New Medical Device Medical device of which structure, usage method, indications, effects or performance is clearly different from those of medical devices already approved Any similar medical device already approved falls into the category of new medical devices and the reexamination period has not been completed. Generic medical device Medical device of which structure, usage method, indications, effects and performance are substantially equivalent to those of medical devices already approved Improved medical device Medical device which does not fall into the category of new medical devices or generic medical devices 23

24 SUBJECT TO PRIORITY REVIEW? New medical device which can be reviewed as a priority over other products according to the provision of Paragraph 7 of Article 14 of the Pharmaceutical Affairs Law; whether to grant the priority review status depends on overall evaluation according to the following 2 criteria. (1) Seriousness of indication A. Disease which significantly affects the life (fatal disease) B. Disease which progresses irreversibly and significantly affects daily living C. Others (2) Medical usefulness A. No existing treatment, preventive measure, or diagnostic method is available. B. The medical usefulness is superior to that of the existing treatment, preventive measure, or diagnostic method in terms of the efficacy, safety, and physical/mental burden on the patient. *Orphan medical devices are subject to priority review. Those who seek the priority review status described above should make a note to that effect in the Remarks column of the application form and attach reasons for considering that the medical device falls into the category of priority review products. For details, see PFSB/ELD (Yakushokushinsa) Notification 0901 No. 1, September 1,

25 CASE STUDY: USE OF PMDA CONSULTATION Clinical trial consultation Clinical trial Pre-development consultation Safety consultation Performance testing consultation Completion of test device Pre-application consultation Regulatory submission Use-results survey Analysis Commitment Development Evaluation Verification/validation testing EXAMPLE: NOBORI Clinical trial consultation (before the Japanese comparative study): To receive guidance/advice about the clinical trial design such as the sample size and endpoints. Pre-application consultation (during the clinical study): To receive guidance/advice about the entire spectrum of nonclinical safety testing and summary of safety logic in animals and humans. Measures taken in response to advice should be described collectively at the end of STED Section 1 History of Development. 25

26 NOTIFICATIONS ETC. RELATED TO APPROVAL APPLICATION The following PMDA website is helpful: Contents related to approval application (5) Definition of priority review Handling of priority review etc., PFSB/ELD (Yakushokushinsa) Notification 0901 No. 1, September 1, 2011 (9) Need for clinical studies Scope etc. requiring clinical study data of medical devices, PFSB/ELD/OMDE (Yakushokuki) Notification No , August 4, 2008 (Overseas clinical study) (2) Points to consider in using overseas data Handling of clinical study data on medical devices which was carried out in foreign countries, PFSB/ELD/OMDE (Yakushokuki) Notification No , March 31, 2006) (3) Supplementary explanation about essential documents Points to consider about Handling of clinical study data on medical devices which was carried out in foreign countries, Administrative Notice, March 31, 2006 (4) Supplementary document about use of overseas data Q&A on Handling of clinical study data on medical devices which was carried out in foreign countries, Administrative Notice, June 23,

27 PROCESS AFTER SUBMISSION: NEW/IMPROVED MEDICAL DEVICE WITH CLINICAL DATA 27

28 PROCESS AFTER SUBMISSION (NEW/IMPROVED MEDICAL DEVICE WITH CLINICAL DATA) External experts Only for new medical devices Applicant Marketing approval application form STED, Technical documents PMDA Presentation Special review discussion I 1) Review Reliability assessment Special review discussion II 1) Review report MHLW PAFSC 2) Approval procedures Approval certificate QMS inspection application form QMS inspection QMS compliance inspection results 1) The frequency and timing of the special review discussion differ from case to case. 2) Deliberated by the Medical Devices and In Vitro Diagnostics Committee of the Pharmaceutical Affairs and Food Sanitation Council (PAFSC), and reported to the Pharmaceutical Affairs Council of the PAFSC (usual pattern) 28

29 Image of Approval Application Package for New Medical Devices Submitted data Medical device approval application form [1] Category [2] Name (generic name and brand name) [3] Intended Use and Indications [4] Shape, Structure, and Principle [5] Raw Materials or Components [6] Product Specifications [7] Operation or Usage Method [8] Manufacturing Method [9] Storage Method and Expiration Period [10] Manufacturing Site of Marketed Product [11] Manufacturing Site of Raw Materials [12] Remarks Instructions for use (draft) etc. Identification of the medical device Summary Technical Documentation (STED) 1. Summary of product 2. Essential Principles and Conformity 3. Device Description 4. Summary of Design Verification and Validation 5. Labelling (draft) 6. Risk Analysis 7. Manufacturing Information Summary of technical documents a. Origin or history of discovery and usage conditions in foreign countries, etc. b. Setting of specifications d. Conformity to the standards stipulated in Article 41, Paragraph 3 of the Pharmaceutical Affairs Law c. Stability and durability e. Performance f. Risk analysis g. Manufacturing method h. Clinical evidence Evaluation data on the quality, efficacy, and safety [Notification] Application form/technical documents: PFSB/ELD/OMDE (Yakushokuki) Notification No , February 16, 2005 STED: PFSB/ELD/OMDE (Yakushokuki) Notification No , February 16,

30 MARKETING APPROVAL APPLICATION FORM FOR Name Category generic name brand name Intended Use and Indications MEDICAL DEVICES Apparatus and Appliances 7. Internal Organ Substitutes Coronary stent ABC Stent Shape, Structure, and Principle Refer to Attachment 1. Raw Materials or Components Refer to Attachment 2. Product Specifications Refer to Attachment 3. Operation or Usage Method Refer to Attachment 4. Manufacturing Method Refer to Attachment 5. Storage Method and Expiration Period Manufacturing Site of Marketed Product Manufacturing Site of Raw Materials Name Name Treatment of patients with symptomatic ischemic heart disease due to de novo coronary artery lesions (lesion length 30 mm) with a reference vessel diameter ranging from 2.5 to 3.5 mm Address Address License or accreditation category Refer to Attachment 6. License or accreditation category License or accreditation No. License or accreditation No. Provide the intended use based on the contents and results of clinical studies. For coronary stents, the vessel to be treated needs to be identified. Provide information on identification of the medical device which was supported by verification testing. Provide if the expiration period is shorter than 3 years. Remarks Specially controlled medical device (Class IV) Single use Medical device marketing authorization holder license number: XXXXX Marketing authorization holder license category: License for marketing Class I medical devices Address of principle place of business: XXXX Application category: new medical device External appearance photograph: Refer to Attachment 7. Instructions for use (draft): Refer to Attachment 8. Provide the following if applicable: Clinical trial notification number, clinical trial consultation number, and new raw materials. For details, refer to the current notification. 30

31 EXAMPLE OF SHAPE, STRUCTURE, AND PRINCIPLE COLUMN Points for description Provide the composition of a single product (e.g., main body and components, type). If the connectivity is ensured by the shape of the connection part, provide necessary requirements for the part (e.g., shape, standards). Principle of operation: Provide a brief description using the JMDN definitions etc. as reference. For medical electrical devices, provide the electrical rating, block diagram, and auxiliary functions (not necessary for the example in this lecture). Example of illustration 1) Drug-eluting stent system Delivery catheter Port [4] Proximal shaft [5] Mid shaft [6] Distal shaft [7] Balloon Drug-eluting stent 2) Drug-eluting stent Cross-sectional diagram of drug elution Type and dimensions of the stent *For the dimensions of the part to be implanted, provide particularly detailed descriptions! 31

32 EXAMPLE OF RAW MATERIALS OR COMPONENTS COLUMN Example of attached specifications Points for description Provide descriptions about the raw materials which correspond to the information in the Shape, Structure, and Principle column. For the component or material which comes into contact with blood, body fluid, mucosa, etc. directly or indirectly through the drug solution, establish the raw material specifications and identify it in detail. Refer to Administrative Notice, PFSB/ELD/OMDE No. 19, dated November 15, For medical devices which are intended to be used in combination with another medical device, simplified descriptions are acceptable. Specification items A. Generic name or common name B. General chemical information 1. Chemical name 2. CAS No., USAN, or CSCL Notification No. 3. Structural formula 4. Molecular weight and others 5. Quantity of low-molecular-weight component 6. Quantity of water-soluble component C. Information from raw material manufacturer etc. 1. Name of manufacturer 2. Product name (or brand name) 3. Manufacturing number or symbol 4. Raw material specifications or product specifications 5. Types and volumes of additives D. Official standard name and number 1. Medical device material standards of JIS, ISO, and ASTM 2. Medical device or drug standards of JP, USP, and EP 3. Other official standards Specification 32

33 EXAMPLE OF PRODUCT SPECIFICATIONS COLUMN Points for description Necessary requirements to ensure the performance/safety of the product submitted for approval Standards/specifications related to the properties/performance or function Performance required to achieve the intended use Standards of the performance specified in the approval standards etc. (performance in Article 6) Except for the performance described above, the function specified for products with other generic names Standards/specifications related to the safety Refer to the intended use, Essential Principles standards, approval standards, etc. for the product submitted for approval. If the shape/structure or raw materials ensure the specifications of the medical device, provide descriptions in the individual appropriate columns. Example of product specifications (Refer to the approval standards for PTCA.) Item Strength of catheter shaft Nominal pressure of balloon Rated burst pressure of balloon Biological requirement Specifications 5 N 0.6MPa 1.2MPa Method for testing or verification Strength of catheter shaft (Annex of ISO ) in Attachment 1 of the approval standards a) Diameter of inflated balloon in Attachment 1 of the approval standards Air tightness/repetitive balloon inflation operability (Annex A of ISO ) in Attachment 1 of the approval standards For materials which come into contact with blood, the biological safety should be ensured according to JIS T Sterility assurance Sterility Assurance Level (SAL):

34 EXAMPLE OF OPERATION OR USAGE METHOD COLUMN Points for description Provide easy-to-understand descriptions of each step of the operation or usage method. If the medical device is intended to be used in combination with another medical device, provide conditions etc. for the medical device that can be used in combination. Clearly provide specific examples of the mate medical device in the package insert. Example of description 1. Preparation before use (e.g., necessary testing, size measurement) 2. Preparation of this product (Provide a device to be used other than this product, if any.) 3. Insertion of this product 4. Expansion of stent 5. Removal of delivery catheter 34 34

35 FORMAT OF STED (1) Format of STED for new medical devices 1. Summary of product 1.1 Overview of product 1.2 Origin or history of discovery and history of development 1.3 Usage conditions in foreign countries 2. Essential Principles and conformity to Essential Principles 2.1 List of referenced standards 2.2 Essential principles and evidence of conformity 3. Device description 3.1 General information (correspondence with generic name, intended use, shape, structure, principle, and operation method) 3.2 Raw materials 3.3 Product specifications 3.4 Storage method and Expiration Period 3.5 Comparison with similar medical devices 4. Summary of pre-clinical design verification and validation documents 4.1 General information (1) Declaration of conformity to standards 4.2 Summary of medical device design validation 4.3 Clinical evidence Format of STED for improved medical devices 1. Summary of product 1.1 Overview of product 1.2 History of design and development 1.3 Usage conditions in foreign countries 2. Essential Principles and conformity to Essential Principles 2.1 List of referenced standards 2.2 Essential Principles and evidence of conformity 3. Device description 3.1 Raw materials 3.2 Product specifications 3.3 Storage method and Expiration Period 3.4 Other information 4. Summary of pre-clinical design verification and validation documents 4.1 Declaration of conformity to standards 4.2 Summary of medical device design validation 4.3 Clinical evidence 35

36 FORMAT OF STED (2) Format of STED for new medical devices 5. Labeling 5.1 Instructions for use (draft) and basis for establishing its content 5.2 Label (draft) 6. Risk analysis 6.1 Implementation status of risk analysis 6.2 Important hazards 7. Manufacturing information 7.1 Manufacturing process and manufacturing site 7.2 Sterilization method 7.3 Quality control Format of STED for improved medical devices 5. Labeling 5.1 Instructions for use (draft) 6. Risk management 6.1 Implementation status of risk management 6.2 Hazards for which safety measures are taken 7. Manufacturing information 7.1 Information on sterilization method 7.2 Information on quality control The STED for new medical devices is required to contain the product information provided in the approval application form as well so that the entire spectrum of the application can be understood with the STED alone. 36

37 STED SECTION 4.3: DESCRIPTION OF CLINICAL EVIDENCE [Summary] For the conducted clinical studies, provide the study type, target patients, sample size, endpoints, clinical trial period, representative study site, and number of sites. Provide and discuss the outline for each study Clinical Trial Results For each study, prepare a list of the study method and outline of study results. Rationale for establishing the subject inclusion criteria, exclusion criteria, usage method, sample size, and control device Breakdown of cases and background information on patients Details and reasons of cases in which the treatment was discontinued and of subjects who withdrew from the study or deviated (list) Explanation about background information on patients Study results of the efficacy and safety and conclusions List of incidence by malfunction type and list of malfunctions (cases) Conclusion Conclusion of Clinical Trial Results Conclusions of the efficacy and safety based on results from each study For Miscellaneous, provide racial differences, indications, long-term results, extrapolation of overseas data, etc. 37

38 APPROVAL CONDITIONS AND USE-RESULTS SURVEY 38 Example of approval conditions New medical devices and reexamination system What is post-marketing surveillance?

39 EXAMPLE OF APPROVAL CONDITIONS Example of approval conditions for new medical devices Use-results survey (mandatory) Report of long-term longitudinal analysis (for example, for 5 years in clinical study patients or those included in the survey) Measures for physicians etc. such as lecture meetings Establishment of criteria for medical institutions, physicians etc.* Set according to the product. * Established in conjunction with academic societies. Approval conditions for 20 new medical devices with published review reports among those approved in 2011 to 2012 Reexamination period Number of products 3 years 16 4 years 1 7 years 3 Total 20 Of them, those requiring all-patient survey Those requiring all-patient survey of a certain period 2 6 Approval condition Number of products Long-term prognosis analysis 8 Lecture meeting 12 Use in well-resourced medical institutions 6 Establishment of criteria for institutions Establishment of criteria for operators Reporting of specific diseases

40 RELATIONSHIP BETWEEN USE-RESULTS SURVEY AND LONG-TERM LONGITUDINAL ANALYSIS Clinical study L Long-term (5-year) follow-up L L L L Approval review Use-results survey (3 years) R R R L L Long-term (5-year) follow-up L L L Reexamination L Longitudinal analysis result Application for reexamination R Annual report of use-results survey 40

41 NEW MEDICAL DEVICES AND REEXAMINATION SYSTEM Target of reexamination (Article 14-4) All new medical devices (devices of which the structure, method of use, indications and effects or performance etc. is clearly different) Application for reexamination The application for reexamination should be filed within 3 months after the expiration of the reexamination period. The application for reexamination should be accompanied by documents on use results, etc. Reexamination period of orphan medical devices: a period of more than 4 years but not exceeding 7 years from the approval Reexamination period of the other medical devices: a period less than 4 years from the approval Post-marketing surveillance When use-results survey is performed, the documents should be collected and prepared in accordance with the standards specified in MHLW Ministerial Ordinance (Ministerial Ordinance on Good Post-marketing Study Practice for Medical Devices [GPSP Ministerial Ordinance]). 41

42 GOOD POST-MARKETING STUDY PRACTICE Conduct in accordance with the Ministerial Ordinance on Good Post-marketing Study Practice for Medical Devices (GPSP Ministerial Ordinance). Outline of GPSP Ministerial Ordinance The surveillance management supervisor (person who supervises the duties) should be assigned. Written operating procedures (e.g., survey, self-inspection, education and training, outsourcing, retention of documents) required for collaboration with the related departments should be prepared. The post-marketing surveillance etc. basic plan and use-results survey implementation plan for each survey should be established. When a survey is conducted, a contract should be concluded with a medical institution in writing and retained. Self-inspection should be performed periodically. Necessary education and training should be provided. After application for reexamination, reliability assessment of technical documents is performed. 42

43 RAPS Japan for Medical Device players since 2008 And

44 RAPS Japan for Medical Device players 44

45 RAPS Japan for Medical Device players RAPS Japan Fundamentals of PAL workshop at TWIns Research Center from 9/2010 1,500+ people ( Industry, Medical Doctors, Scientists, and Ministry) participated by now. 4-5 senior lecturers team up to run every lesson together and respond to all questions

46 Ms. Shiho Tanaka ( She cooperated to publish our book, too.) Section Manager, MAH Responsible Manager RA Submission Group Medtronic Japan Co., Ltd. RAPS Japan Operating Member Mr. Katsunori Ishiguro Senior Research Fellow, Medical Device Strategy Institute (MDSI) Japan Association for the Advancement of Medical Equipment (JAAME) Mr. Tomoki Hasegawa Manager, New Products Development & Regulatory Affairs Div. Smart Practice Japan Ms. Miwa Kato, R.Ph. Head of Regulatory & Quality Hologic Japan, Inc. Ms. Misako Takahashi. Executive Assistant RAPS Japan 46