Global Regulatory Partners GK

Current Capabilities in Japan

Company Profile ▪ Global Regulatory Partners GK (GRP Japan) is the Japanese affiliate of Global Regulatory

Partners US (GRP US)

▪ GRP US was established in 2010 and is headquartered in Massachusetts (Boston area) USA.

▪ GRP Japan was established in 2016 and is based in Tokyo, Japan

▪ GRP Japan is licensed as MAH category I for medical devices & drugs and MAH for IVDs.

▪ Total staff is 64 = 26 senior management (4 in Japan)

▪ Key personnel have Ph.D. or Master degrees and more than 15 years’ experience in the pharmaceutical and biotechnology industries

Vision & Strategy

Focus on early stage and medium size life science companies

01Be a one (1) stop shop for Regulatory Affairs, Safety, Quality Services

02Offer tailored services that meet companies’ need.

03Cover the whole products lifecycle, from concept till commercialization.

04

GRP GK MAH/DMAH Services▪ GRP Japan provides the following services:

Foreign Manufacturing site Accreditation (FMA)

Pharmacovigilance

Regulatory affairs services Reimbursement Quality Services ICC (In Country Care-taker)

▪ GRP GK is licensed by local authorities as MAH/DMAH category 1 and can represent

any foreign medical device/IVD and drug company in Japan.

▪ As MAH/DMAH, GRP GK complies with all Japanese requirements outlined in Act No.

145, Article 23-2-1/Article23-2-17.

MAH/DMAH Responsibilities

In Japan, GRP is licensed as Category I MAH.

MAH/DMAH services:▪ Importation of products▪ Product registration▪ Product quality and safety assurance▪ Product storage in an establishment with MAH licensing▪ Product release to distributors or other sales groups▪ Post-market vigilance

Registration Flow Chart for MD

Step 1 • FMA/FMR : Foreign Manufacturing Registration

Step 2 • PMDA Meeting (if necessary)

Step 3 • Clinical Trial (if necessary)

Step 4 • Registration Dossier Submission and QMS Application*

Step 5 • Approval/Certification/Notification

Step 6• Application for Reimbursement

* It is not necessary for most of Class I product

Foreign Manufacturing Sites Accreditation: FMA

▪ Foreign Manufacturers need to register their manufacturing sites before importing their devices to Japan according to the requirements of Act No. 145, Article 23-2-4.

▪ Sites to be registered : Design Facility, Main Assembling Plant, Sterilizing Facility.

▪ Required documents for registration:- Form No. 63(5) (related to MHLW Ordinance No. 1 in 1961 Article 114-15) - Personal History of Responsible Person - Self-Declaration- Document of buildings and facilities - ISO13485 certificate (preferable)

Regulatory Affairs Services

⮚ Regulatory Strategy⮚ Preparation of meeting with PMDA⮚ Device registration in compliance with the

requirements of Act No. 145, Article 23-2-5)⮚ Device registration process

- Device classification

- Registration of device Class I- Registration of devices Class II, Class III and Class IV

Classification of Medical Device in Japan

Class Definition

Class I : General medical devices

The risk to customers in the event of malfunction is regarded as almost negligible.Registration category: NotificationSelf Declaration (submission to PMDA)

Class II : Controlled medical devices

The risk to customers in the event of malfunction is regarded as relatively low.Registration category: Certification or ApprovalCertified by Registered Certification Body or Approved by PMDA

Class III: Specially controlled medical device

The risk to customers in the event of malfunction is regarded as relatively high.Registration category: Approval or CertificationApproved by PMDA or Certified by Registered Certification Body

Class IV: Specially controlled medical device

The device is high invasive with potential fatal risk to customers.Registration category: ApprovalApproved by PMDA

Registration of Class I Devices

The content of the notification for Class I devices is as follows: Classification General name Sales name Purpose of usage and effect Figure, machinery and principle Raw materials Standards concerning performance and safety Usage

Storage conditions and Expiry Manufacturing process Manufacturing site Package inserts Photograph of product appearance Suitability rational for definition of

general name

9. Storage condition and expiry10. Manufacturing process11. Manufacturing site (name of the place and

registered number)12. Package inserts13. QMS compatibility confirmation14. STED*

Registration Dossier for Class II-IVContent of registration dossier for Class II, Class III and Class IV devices

1. Classification2. General name3. Sales name4. Purpose of usage and effect5. Figure, machinery and principle6. Raw materials7. Standards concerning performance and safety8. Usage

Content of the Registration Dossier of STED*List of requirements List of requirements1. Summary of Product

1.1 Overview of Product1.2 Origin or History of Discovery and History of Development1.3 Usage Conditions in Foreign Countries

4.2.1.2 Electrical Safety and Electromagnetic Compatibility4.2.1.3 Biological Safety4.2.1.4 Radiation Safety

4.2.1.5 Mechanical Safety4.2.1.6 Stability and Durability

4.2.2 Tests to Support Performance4.2.3 Tests to Support Efficacy4.2.4 Tests to Support Usage Method

4.3 Clinical Evidence4.3.1 Clinical Trial Results4.3.2 Conclusion of Clinical Trial Results4.3.3 Miscellaneous

2. Essential Principles and Conformity to the Essential Principles2.1 List of Referenced Standards2.2 Essential Principles and Evidence of Conformity

5. Labeling5.1 Instructions for Use (Draft) and Basis for Establishing Its Content5.2 Label (Draft)

3. Device Description3.1 General Information3.2 Raw Materials3.3 Product Specifications3.4 Storage Method and Expiration Period3.5 Comparison with Similar Medical Devices

6. Risk Analysis6.1 Risk Analysis System6.2 Important Hazards

4. Summary of Pre-clinical Design Verification and Validation Documents

4.1 General Information4.2 Summary of Medical Device Design Validation

4.2.1 Tests to Support Safety4.2.1.1 Physical and Chemical Properties

7. Manufacturing Information7.1 Information on Manufacturing Process and Manufacturing Site7.2 Sterilization Method7.3 Quality Control

Quality Services⮚ Quality Audits of manufacturers, suppliers and distributors in Japan according

to MHLW ordinance 169 in 2004, FDA 21 CFR 820 or ISO 13485.

⮚ Preparation for PMDA pre-approval inspection and FDA inspection (gap

analysis, mock inspection, training) and response to FDA after inspection.

⮚ Creating Quality Manual and SOPs

⮚ Implementation of Quality system

⮚ Products release in Japan

Content of QMS Application▪ QMS (MHLW Ordinance No. 169 in 2004, MHLW Ordinance No. 94, 2014)▪ QMS compliance inspection can be performed either on desktop/document or

on-site ▪ Content of QMS application includes :o Product application document (photocopy) for manufacturing and sales approvalo ISO13485 certification or Inspection report issued by registered certification bodies in Japan or

by recognized foreign health authorities under within 3 years. o Manufacturing process flowo Outline of contents of MAH/RMS (Registered Manufacturing Site) activities and documents

which can identify mutual relations of QMS between MAH and RMSo Summary of Planto Child Products List

QMS Inspection (Pre-, Post-)

R&D

Application for Approval

RegulatoryReview

Approval

Marketing

Every 5 years

Post-approval inspection

Pre-approvalinspection

Post-approvalinspection

One of the requirements for marketing Approval of medical device

Conducted every 5 years after Marketing approval

Based on applicationConducted per Product Family

PRE-MARKETING SAFETY▪ Receipt, data entry, review, analysis, coding

and follow up on serious adverse events (SAEs) and

▪ (SUSARs) from clinical studies.

▪ Provide safety input to protocols, clinical study reports and investigator brochures.

▪ Safety data reporting to competent authorities, ethics committees and investigators.

POST-MARKETING SAFETY▪ Collection, evaluation and review of

complaints.

▪ Medical Safety Assessment of individual Case Reports.

▪ Adverse events reporting PSUR preparation and submission.

▪ Health Authorities PV databases monitoring.

▪ Products Safety profile building and continuous update.

Safety/Pharmacovigilance Services

PharmacovigilanceGVP Reporting activities in JapanICSR (individuals case safety report for domestic and foreign issues) Two categories in ICSR

1. Medical device defect2. Infection (equal to contamination)

Two types of information are required in ICSR for Medical device. (different from drugs)*AER and Device defects1. Devise defects with no AERs should also be reported if the defect has possibility to develop serious adverse

events2. Difference in timelines of ICSR between foreign and domestic (Japanese) cases.

Research Report There is another expedited report (Research Report) other than ICSRs Source of Research Report are:

1. Scientific literatures and presentations at scientific meetings (Japan and foreign) 2. Actions taken for safety measures (recall, disposal, stop manufacturing ) in foreign countries

Annual Reports 1. Unexpected non-serious individual cases are reported annually as periodical report.

▪ There are three categories (A, B & C) of MD

A1: ComprehensiveThe technical fee comprises the cost of MD(e.g., sutures, gauzes)

A2: Specifically comprehensiveItems that are evaluated comprehensively inspecific categories (e.g., PET, CT, MRI)

B: Individual evaluation (reimbursable MD)Device prices that are individually determined and evaluated. It is usually called as SpecialTreatment Medical Device (STM).(e.g., pacemakers, artificial joints)

C1: New-function productsProducts that need a new function classification and have already been evaluated for technical fee(e.g., drug eluting coronary stents) C2: New-function/technology productsProducts that need a new functionclassification and have not yet beenevaluated for technical fee(e.g., implantable artificial hearts)F: Material and products not suitable for

reimbursement for health insurance

Reimbursement of Medical Devices

▪ Time-line of ReimbursementA1: Comprehensive

20 days after submission of the applicationA2: Specifically comprehensive & B: Individual evaluation

First day of the next month for applications submitted by the10th day of each month

- automatically determined using current fees-

C1: New-function products & C2: New-function/technology productsIt takes 4 months for C1 and 5 months for C2 from submission toapproval by Chuikyo*, respectively except objection raised case. Listing will be done 4 times a year (March, June, September, December)

- determined by the Chuikyo* through medical device special committee -* Central Social Insurance Medical Council of MHLW

Reimbursement of Medical Devices

+Note: These timelines do not include the time lines needed for the preparation of the submission

Procedure for Medical Device Reimbursement

Submission for a “request for health insurance reimbursement*”

Objection RaisedNo Objection

Approval by the Chuikyo (Central Social Insurance Medical Council of MHLW)

Medical Device Specialist Committee

1. Presentation needs to be made to Medical Economics Division

2. Meeting with Medical Economics Division3. Submission of confirmation note of the findings4. Presentation needs to be made to the Medical

Device Specialist CommitteeExamination of Applications

Notification of the draft decision

C1/C2

Listing in the National Health Insurance Reimbursement

A1/A2/B

Submission of complaint formMedical Device Specialist Committee the 2nd

Non-applicable

or F

4-5 months

1-3 months

20-50 days

▪ GRP Service Contents: 1) Make an Application form of Drug Master File2) Apply for and maintain DMF3) FMA application and maintenance4) Communicate with foreign manufacturer and represent

of the foreign manufacturer in Japan5) Communicate with PMDA and respond to the inquiries6) Communicate with MAH or distributors in Japan7) Perform ICC maintenance work

ICC (In Country Care-taker)

Thank You

Dr. Suzan Davis

Global Regulatory Partners Inc. & GK

info@globalregulatorypartners.com

(USA) +1 781-672- 4200(JP) +81 3 4360 9287

ありがとうございました