MDC Japan 1

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

April ２００8．Medical Device Consulting Japan Japan EU US 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)

Population: 493 million, 27 countries EC unit F3：Medical 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.

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 UL、TUV America, TUV/RH, BSI etc

Laws and Regulations

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)

90/385/EEC Active Implantable Medical Devices Directive（AIMDD） 93/42/EEC Medical Devices Directive（MDD） 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) 98/47/EEC Revised Medical Devices Directive (revised in September 2007) The following contents are mainly mentioned on MDD.

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) §820 Quality System Regulation (QSR) Many Guidelines related to CFR Recognized Consensus Standards

License and/or Registration of each type of Business

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 ClassⅡ- Class Ⅳ

MDs and Registration for sales of ClassⅠ 5. License for Repair Business of each Technical Support Office

Registration of Representative Authority (Initial Distributor in EU) Registration of Manufacturer and List of Device Category and Products Number of Japanese manufacturers registered is about 350 – 400.

Initial Registration of Device Establishment ：Manufacturer including Foreign Manufacturer and Initial Importer shall be registered into FDA File. Annual Device Listing of the manufacturer shall be provided to FDA/CDRH Number of Japanese manufacturers registered is 605 as of Oct. 2007.

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Japan EU US

IVD is included in the category of Medical Device. Although 2000 MDs were classified under Old PAL, 4000 MDs have been defined based on GMDN and classified. into 4 classes under New PAL, so many devices are newly included as MD and about 200 MDs were changed from Class Ⅰto higher classes, so called Class-Up MDs.

Annex 8 Medical Device Classification Class Ⅰ, Ⅱa,Ⅱb, Ⅲ

§862 – 892 Medical Device Classification : ClassⅠ,Ⅱ,Ⅲ General Controls: Common controls for all medical devices, such as Initial Registration of Device Establishment and Initial Importers, Device listing, GMP/QSR etc

Class Ⅰ（General Medical Device ：Malfunction causes only minor effect on human body）

: X-ray film, surgical steel knife etc are required Notification only.

Class Ⅰ: 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

ClassⅠ: X-ray tubes, Vacuum Tubes, etc 510(k) (Pre-market Notification) is not required except specific devices.

ClassⅡ（Controlled Medical Device：Malfunction 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

ClassⅡａ : 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

ClassⅡ: 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.

Classification of MDs and

Requirements for Marketing Clearance

Class Ⅲ (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 Ⅱｂ :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

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Japan ＥＵ US Class Ⅳ (Highly Controlled Medical Device : Invasive Device

of which malfunction may cause life threatening effects): Implantable pace maker, stent etc. shall comply with Essential Principles and be applied to PMDA.

Classification and Requirements for Marketing 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

Class Ⅲ : Implantable MDs in heart or Central Nerve etc. Annex 2 including Sec. 4 or (Annex 3 + Annex 4 or 5) 1. Clinical Investigation approved by Competent

Authority of Member State 2. Certification for Full Quality System of the

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 Ⅲ (Implantable MDs, Vascular Stent, Artificial Heart and New MD etc) : is required to meet General Controls, approval of

IDE(Investigational Device Exemption for Clinical Study) and PMA (Pre-market Approval) with submission of documents for each of 4 modules

Class Ⅱ: MDs with Certification Standard (JIS) shall be reviewed and

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 Ⅲ: 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 Ⅱａ, Ⅱｂ 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 Ⅱ： 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 Ⅳ: 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.

Time scale to get Marketing Clearance

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.

Class Ⅲ, depending on period of Clinical Investigation and Type Test by NB Clinical Investigation (MDD Article 15) is

required for Class Ⅲ and Implantable/ invasive Class Ⅱａ orⅡｂ MEDDEV 2.7.1 : Talks about evaluation of

medical device clinical data

Class Ⅲ： IDE + Clinical Study takes 6 months – 2 years After submitting application documents of 4 modules for PMA to FDA, it takes min. 6 months and average 8 months to get approval depending on the report of Clinical Study, quality of documents and response to FDA. and the result of PMA Inspection for manufacturer

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Japan ＥＵ US Quality Management System/GMP

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 ⅡMD with Certification Standard (JIS) is audited by RCB. Manufacturers of ClassⅡMD without JIS or Class Ⅲ or Ⅳ

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.

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

21 CFR 820 QSR（Quality 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)

Adverse Event or

Incident Report to

Competent Authority

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) The number of the report is increasing, because penalty for

violation was enforced strongly In 2002 5,252 reports In 2004 16,000 reports

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 manufacturer established a link between the device and the event but not later than 10 elapsed calendar days following the date of awareness of 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

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Japan EU US

Recall and Removal

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

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

Recall to FDA （Ｃｏｒｒｅｃｔｉｏｎｓ ａｎｄ Ｒｅｍｏｖａｌｓ） Classification of Recall : Ⅰ(most urgent and important) →Ⅱ→Ⅲ Number of Recall in 2005 was 571 In 2006 was 630