Comparing Medical Device Law & Regulations of Japan, EU and US

Japan Competent Authority, Related Organization Population: 127 million Ministry of Health, Labor and Welfare( MHLW), -Pharmaceutical and Food Safety Bureau, - Office of Medical Device Control - Office of Compliance - Pharmaceutical Affairs office of each Government Prefectures - Review and Audit by Pharmaceutical and Medical Device Agency PMDA: about 30 specialists Registered Certification Body (RCB) :14 (JQA, TUV/RH TUV/SUD, BSI, UL, SGS etc) Pharmaceutical Affairs Law (PAL) New PAL promulgated in July 2002, enforced as of April 1, 2005 to harmonize with GHTF and adopt Quality Management System (QMS), and Essential Principles. PAL Enforcement Ordinance, PAL Enforcement Regulation, GQP (Good Quality Practice)GVP (Good Vigilance Practice)QMS (Quality Management System) and GCP (Good Clinical Practice) promulgated in July 2004 July 2005. Many Ordinances and Notices issued up till now. Transfer of Certification or Approval (KISAI-SEIBI: June 8, 2007) for medical devices approved or notified under Old PAL must be done until the next renewal of license of MAH (2006 March 2010) Technical Standards (JIS) for Certification (396) , Approval (35) and IVD Reagent Certification (8 groups, 366) The following Licenses are required for MD business, 1. License for Manufacturer (4,269 as of 2007) 2. Accreditation of Foreign Manufacturers (about 1,000) 3. License for Marketing Authorization Holder (MAH: 2,676) who is responsible for marketing medical devices and was Manufacturer or Importer of MDs under Old PAL. 3 controllers are required, Marketing Supervisor, Safety Control manager, Quality Assurance manager (quite unique compared with US, EU) 4. License for Retail and Rental Business of Class- Class MDs and Registration for sales of Class 5. License for Repair Business of each Technical Support Office MDC Japan April 8Medical Device Consulting Japan EU Population: 493 million, 27 countries EC unit F3Medical Device & Cosmetic Competent Authority of each Member States Notified Body (NB) : About 70 (BSI, TUV/RH, TUV/SUD, KEMA, etc) Notified Body (NB) in Japan: BSI, TUV/RH, TUV/SUD, SGS ,etc. 90/385/EEC Active Implantable Medical Devices DirectiveAIMDD 93/42/EEC Medical Devices DirectiveMDD 98/79/EEC In Vitro Medical Devices Directive IVDD Essential Requirements of each Directives Harmonized Standards (EN,IEC,ISO) MEDDEV Guidance Documents : Vigilance Guidance MEDDEV 2.12-1 Rev 5 (effective from Jan..1, 2008) Food, Drug and Cosmetic Act of 1938 1976 Medical Device Amendments (MDA) 1990 Safe Medical Device Act 1997 FDA Modernization Act 2002 Medical Device User Fee and FDA Modernization 21CFR: Code of Federal Regulation, Food and Drugs 801 Labeling 807 Establishment registration and device listing for manufacturers and initial importers of devices 814 Pre-Marketing Approval (PMA) 98/47/EEC Revised Medical Devices Directive (revised in September 2007) 820 Quality System Regulation (QSR) The following contents are mainly mentioned on Many Guidelines related to CFR MDD. Recognized Consensus Standards Registration of Representative Authority (Initial Initial Registration of Device Establishment Distributor in EU) Manufacturer including Foreign Manufacturer and Registration of Manufacturer and List of Device Initial Importer shall be registered into FDA File. Category and Products Annual Device Listing of the manufacturer shall be provided to FDA/CDRH Number of Japanese manufacturers registered is about 350 400. Number of Japanese manufacturers registered is 605 as of Oct. 2007. US Population: 303 million FDA (Food & Drug Administration) CDRH (Center for Devices and Radiological Health) : about 1,000 reviewers and specialists Review of 510(k) by Third Party Accredited Bodies such as ULTUV America, TUV/RH, BSI etc

Laws and Regulations

License and/or Registration of each type of Business

Japan IVD is included in the category of Medical Device. Although Classification of 2000 MDs were classified under Old PAL, 4000 MDs have been MDs and defined based on GMDN and classified. into 4 classes under Requirements New PAL, so many devices are newly included as MD and for Marketing about 200 MDs were changed from Class to higher classes, Clearance so called Class-Up MDs. Class General Medical Device Malfunction causes only minor effect on human body : X-ray film, surgical steel knife etc are required Notification only. ClassControlled Medical DeviceMalfunction raises low possibility of life threatening effect or serious injury : About 400 MDs with Certification Standard (JIS) : X-ray, CT, Ultrasound, EKG, Endo-scope etc shall comply with the applicable standard and Essential Principles which are same to Essential Principles of GHTF and be applied to Registered Certification Body (RCB) . MDs without JIS shall comply with Essential Principles and be applied to PMDA

EU Annex 8 Medical Device Classification Class , a,b,

Class : Annex 7 Technical File of the MD, Declaration of Conformity by the manufacturer and CE Marking. Serialized MD and measuring MD must be certified by NB Class : Annex 7 + Annex 2 or (Annex 4 or 5 or 6) 1. Certification for Full Quality System (ISO 13485) of the manufacturer by NB 2. Technical File of the MD to show compliance with Essential Requirements and inspection by NB 3. Declaration of Conformity by the manufacturer 4. CE Marking

US 862 892 Medical Device Classification : Class ,, General Controls: Common controls for all medical devices, such as Initial Registration of Device Establishment and Initial Importers, Device listing, GMP/QSR etc Class: X-ray tubes, Vacuum Tubes, etc 510(k) (Pre-market Notification) is not required except specific devices.

Class: Substantial equivalence to other products (Predicate Device) in commercial distribution, such as Diagnostic X-ray system, Ultrasound, CT, MRI, EKG etc 510(k) submission needs the device name, the establishment registration number, the class, action taken to comply with the requirements of the act for performance standard, proposed labels, labeling and documents indicating the device is substantially equivalent to predicate devices . For medical device contained Software, manufacturers must submit the documents of the Software including Risk Analysis and Verification & Validation Data.

Class (Highly Controlled Medical Device : Malfunction cause substantial effect on subjects) : Dialyzer, Radio-therapy system, Respirator, etc MDs shall comply with Essential Principles and be applied to PMDA. MDs with Approval Standard (35 Std.) shall comply with the standard and Essential Principles Depending on the intended use and materials Bio-compatibility test, Sterilization Validation and/or Clinical Study are required.

Class :Diagnostic X-ray, CT, etc.: Annex 7 + Annex 2 or (Annex 3 + 4 or 5 or 6) 1. Certification for Full Quality System (ISO 13485) of the manufacturer by NB 2. Technical File of MD to show compliance with Essential Requirements and inspection by NB 3. Declaration of Conformity of the MD by the manufacturer with Technical File 4. CE Marking

MDC Japan

Japan Classification Class (Highly Controlled Medical Device : Invasive Device and of which malfunction may cause life threatening effects): Requirements Implantable pace maker, stent etc. shall comply with for Marketing Essential Principles and be applied to PMDA. Clearance New MDs are required GLP (Good Laboratory Practice, Pre-Clinical tests) and Clinical Study based on GCP Notice Remark points on Application for Marketing Approval for Medical Devices (No. 0216001, dated Feb. 16. 2005) Attachment 1 shows the list of example of Medical Devices required Clinical Study Time scale to Class : get Marketing MDs with Certification Standard (JIS) shall be reviewed and Clearance QMS of the manufacturer shall be audited by Third Party Certification Body. Certification time is 1 3 months depending on quality of documents and QMS. Certification Fee is less than 1 million yen depending on RCB and numbers of application per year Class : MDs with and without Approval Standard shall be reviewed by PMDA and the QMS shall be audited by Inspectors of each Government Prefecture. Approval Time is 6 to 18 months. Review fee without JIS of PMDA is 1,232.8 kyen. Review fee with JIS of PMDA is 351.4 kyen. Class : shall be reviewed by PMDA, review time depends on the quality of application documents and QMS. The review fee for approval is 3,741 kyen excluding consultation fee by PMDA. New MD: Period for Clinical Study is 1 3 years depending on the intended use and number of applicable patients. Review fee of GLP & Clinical Study of PMDA is 2,697.7 kyen. Cost of Clinical Study is 10 million 100 million yen.

US Class (Implantable MDs, Vascular Stent, Class : Implantable MDs in heart or Central Nerve etc. Annex 2 including Sec. 4 or (Annex 3 + Artificial Heart and New MD etc) : is required to meet General Controls, approval of Annex 4 or 5) IDE(Investigational Device Exemption for 1. Clinical Investigation approved by Competent Clinical Study) and PMA (Pre-market Authority of Member State Approval) with submission of documents for 2. Certification for Full Quality System of the each of 4 modules manufacturer by NB 3. Type Test of the MD for Essential Requirements by NB 4. Review Design Dossier of the product and Pre-market inspection by NB, then Approval of CE Marking Class , Audit of ISO 13485 and inspection of compliance of MDD by NB; Audit of NB takes 3 5 days depending on the size of manufacturer and quality of Technical File etc of the MDs Class After submitting documents for 510(k), it takes 2 6 months to get clearance depending on the quality of the documents and response to questions from FDA or Third Party.

Class IDE + Clinical Study takes 6 months 2 years After submitting application documents of 4 Clinical Investigation (MDD Article 15) is modules for PMA to FDA, it takes min. 6 months required for Class and Implantable/ invasive and average 8 months to get approval depending on the report of Clinical Study, quality of documents Class or and response to FDA. and the result of PMA MEDDEV 2.7.1 : Talks about evaluation of Inspection for manufacturer medical device clinical data

Class , depending on period of Clinical Investigation and Type Test by NB

MDC Japan

Quality Management System/GMP

Adverse Event or Incident Report to Competent Authority

Japan Manufacturer must establish QMS based on New QMS Regulation (almost equivalent to ISO 13485) Marketing Authorization Holder must establish QMS based on GQP and Post Marketing Vigilance System based on GVP. Manufacturer of Class MD with Certification Standard (JIS) is audited by RCB. Manufacturers of ClassMD without JIS or Class or is audited by inspectors of Government Prefecture Manufacturers of New MD is audited by PMDA The QMS of Foreign Manufacturer will be audited by PMDA or RCB based on QMS regulation. At every application for Certification or Approval for MD QMS audit is done for the manufacturer of MD. It is quite unique and too much cost. Adverse Event or Incident Report: Chapter 10 of PAL Enforcement Regulation When Marketing Authorization Holder notices any of the following cases, they shall inform the Minister and PMDA within the period specified in each item, (1) 15 days report of death, which are suspected to be due to faults of the medical device or the medical device used in foreign country, or the occurrence of cases attributable to infection diseases suspected to be associated with the use of the medical device, etc. (2) 30 days report of the occurrence cases such as Disabling, potential leading to death or disabling etc. (See Chapter 10, Article 253 about detail)

Quality Management System (ISO13485) : Audit for manufacturer and Certification by NB

US 21 CFR 820 QSRQuality System Regulation : Almost same to ISO 13485 Audit for manufacturer by FDA takes normally 3 5 days depending on the size and quality of manufacturer FDA audit focuses to Management Responsibility, Design Control including Risk Analysis, Process Validation, Complaint Handling and Corrective and Preventive Actions (CAPA)

Incident Report and Recall (Article 10 of MDD) and Vigilance Guideline MEDDEV 2.12-1 Rev.5 1. Old MEDDEV requires reporting Incidents within 10 or 30 days., now replaced by immediately 2. Incident and Event Reporting to relevant Competent Authority (CA) 1) Serious public health threat : Report immediately (without any delay that could not be justified) but not later than 2 calendar days after awareness by the manufacturer of the threat. 2) Death or Unanticipated serious deterioration in state of health : Report immediately (without any delay that could not be justified) after the The number of the report is increasing, because penalty for manufacturer established a link between the violation was enforced strongly device and the event but not later than 10 elapsed In 2002 5,252 reports calendar days following the date of awareness of In 2004 16,000 reports the event 3) Others : Report immediately (without any delay that could not be justified) after the manufacturer established a link between the device and the event but not later than 30 elapsed calendar days following the date of awareness of the event 3. Reporting of use errors to relevant CA

MDR (Medical Device Reporting) : CFR 803 Manufacturers are required to report an individual adverse event (MDR) to FDA from becoming aware of an event as follows, 1) 5 day reports on events that require remedial action to prevent an unreasonable risk of substantial harm to the public health and other types of events designated by FDA 2) 30 day reports of deaths, serious injuries that is life threatening, even if temporary in nature and malfunctions MDR in 2005 17,000 MDR in 2006 20,000

MDC Japan

Japan Recall Removal Marketing Authorization Holder must report to Government and Prefecture and PMDA in case of Recall and Removal Class (most urgent and important) In 2005 number of Recall was 322 In 2006 was 365

EU Field safety Corrective Action (FSCA) and Field Safety Notices (FSN) 1) Recall Notice now replaced by FSCA ,but covers recall as well 2) FSCA should be notified to relevant CA and NB via FSN 3) If recall is ordered outside EU but product sold in EU, FSCA must be notified to relevant CA

US Recall to FDA Classification of Recall : (most urgent and important) Number of Recall in 2005 was 571 In 2006 was 630

MDC Japan