overview of licensing and product approval processes for ... · three pillars of product release to...

Overview of licensing and product approval processes for IVD reagents in Japan

7th Joint Conference of Taiwan and Japan on Medical Products Regulation

Chang-Yung Fa Convention Center

October 1, 2019

1 Oct, 2019 - 7th Joint Conference of Taiwan and Japan on Medical Products Regulation

Agenda

1. Outline of IVD Regulatory System in Japan

2. Guidance for Registration of IVD


Basic Requirements for Japanese IVD Regulations

Summary of IVD Regulations

Diagnosis of Disease

IVD Reagents/Instruments

Drug Medical Device

To be used for diagnosis, but it does not directly touch human or animal body.


Main Reactive Raw Materials Other Raw Materials

Formulation

Filling into container

Packaging & Labelling

Combination

In Vitro Diagnostic Reagents

Filling into container

Reagents

Packaging / Label / Storage

Storage of final

Manufacturing process registered as IVD manufacturing industry

Manufacturing Flow Chart


Formulation


Three Pillars of Product Release to the Market

Review of legal manufacturer

Review of product efficacy and safety etc.

Review of manufacturing and quality management systems (QMS)

Domestic manufacturers

Foreign manufacturers

R&D, mfg, risk assessment, etc.

Manufacturing outsourcing/ entrusting agreement (Subsequent applications are submitted by the

subcontractor)

<Manufacturing outsourcing>

(1) Application for marketing license

(2) Application for marketing approval

(3) Application for manufacturer registration

(4) Application for foreign manufacturer

registration

Review on products (PMDA)

Registration

On-site / document-based audit by

LOCAL AUTHORITY

On-site / document-based audit by

PMDA

Registration

Application for QMS Compliance Investigation

On-site (Document-based) audit

Obtaining marketing

license


Agenda

1. Outline of IVD Regulatory System in Japan

2. Guidance for Registration of IVD


１．Research and Development Phase

２．Manufacturing and Marketing License Phase

Manufacturing and Marketing License for IVD Reagents (Incl. Foreign Manufacturer)

Regulatory Submission

３．Post-Marketing Safety Control

(GVP; Good Vigilance Practice)

Summary of IVD Regulation



Marketing License （製造販売業）

Application of Pre-Marketing Approval (Certification)

Reimbursement Request

Manufacturing License (製造業)

Release to the market

Notification

Listed on National Health Insurance IVDs

QMS Conformity Assessment

Manufacturing and Marketing Licenses to Product Registration

Approval (Certification)


Class Definition Standard Review

Categories

Class I Low risk and Reference Material Listed on the Official Gazette e.g. Amino acids, hormones, minerals, enzymes

• Conformity to Standards

Notification

Class II Low risk and No Reference Material Listed on the Official Gazette e.g. Hormone, enzymes, allergy (IgE) , auto-antibodies

• Conformity to Standards

Notified Body Certification

Class III Middle and High Risk and the accuracy of the product is considered to have a significant impact in sustaining life. e.g. Bacteria, viral antigens, human genome, tumor markers, companion diagnostic tests

• Novel Analyte • Conformity to

Standards • Non Conformity to

Standards • No Standards

Ministerial approval, reviewed by PMDA

Classification and Examination Categories for IVD Reagents


Flow from R&D to marketing approval

Performance Evaluation Sensitivity, Accuracy, Reproducibility Storage stability Interference of specimen (endogenous materials, Cross

reactivity, etc.) Method comparison (me, too product) Clinical evaluation test (novel product) Others

RA Submission

1. Preparation for submission

Other Information Intended use Assay principle Critical raw materials for reaction High risk materials e.g. poisonous and deleterious substances animal origin Others


Review by Authorities

Categories Objective Regulatory Authority

Approval 承認/Shonin

• Novel analyte

• Meet to Approval Standards (Class III)

• No Standards (Class III)

• Non Conformity to Standards (Class I/II/III)

Ministerial (reviewed by PMDA)

Certification 認証/Ninsho

• Certification Standard Products (Class II) Notified Body

Notification 届出/Todokede

• All others which are not “Approval” or “Certification” (Class I)

PMDA

2. Which route of submission?



Supplementary Notices

Response Letters

3. What’s reviewed by PMDA


Product validity as IVD reagents Performance characteristics, clinical utility, etc.

Product Design Performance, effectiveness, safety

Controls Quality control, safety controls

Others

Additional requests Data Correction on format/wording Others

Go to next


Approval/Certification

Expert Meeting Including External Experts

Novel analyte Specific PMDA approval products

Completion Document Review



Contents JapanTaiwan

Class II

Taiwan

Class IIIJapan

Taiwan

Class II

Taiwan

Class III

Packaged Insert ○ ○ ○ Packaged Insert

Label × ○ ○ -

Product photo × ○ ○ -

IFU × ○ ○ -

Service Manual × ○ ○ -

Background and history of development ○ × × - -

Status of use in domestic and foreign countries ○ × ○ - STED

Clinical significance of IVD ○ × × - -

Measurement method (Priciple, Procedure, Judgment) ○ × ○ - STED

Information for main ingredient ○ × ○ - STED

Equivalency to existing products ○ × ○ - STED

Sensitivity as quality control methods ○ × × - -

Accuracy as quality control methods ○ × × - -

Repeatability test as quality control methods ○ × × - -

Calibration and traceability ○ ○ ○ 8. Pre-clinical study 8. Pre-clinical study/ STED

Shelf life stability ○ ○ ○ (c) Stability

In-Use stability (Open vial stability, On-board stability etc) × ○ ○ -

Transportation stability × × ○ - -

Declaration of Conformity ○ × ○ -

Essential Principles checklist ○ × ○ -

cut-off value △ △ △

Measurement range △ △ △

LoD, LoB, LoQ △ △ △

Spike test as Performance △ × × - -

Dilution test as Performance ○ × × - -

Sensitivity ○ △ △

Reaction specificity (interferences, cross reactivity, etc) ○ △ △

Correlation with existing products △ ○ ○

Setting of Measurement procedure and condition ○ × × - -

Tests using seroconversion panels, etc. (for HIV, HCV,

HTLV, HBsAg)△ × △ -

Preciion (Repeatability, Reproducibility) × △ △ -

Accuracy (Trueness etc) × △ △ -

CB test report × △ △ -

EMC test report × △ △ -

Software validation document × △ △ -

Clinical performance study results △ △ △ (h) Clinical performance study 11.Clinical trial reports 11.Clinical trial reports/ STED

System for Risk management ○ × ○ -

Important hazard and risk management (riskmanagement

worksheet)○ × ○ -

Supportive data shows human blood derived material is

negative or inactivated for HIV, HCV, HBV○ ○ ○ 8. Pre-clinical study/ STED

SDS × ○ ○ - 8. Pre-clinical study/ STED

Manufacturing process ○ ○ ○ 8. Pre-clinical study 8. Pre-clinical study/ STED

Manufacturing site ○ × × - -

SOP and CoA for for the active ingredient(s), raw

materials derived from human and animals and the final

product

× ○ ○ - 8. Pre-clinical study 8. Pre-clinical study/ STED

Specification and analytical methods of active ingredient

andsemi-finished product× × △ - -

Specification and technical information of final product. × × ○ - -

Manufacturing and purification process of final product × × △ - -

Process Control or Batch Production Records × × ○ - -

Free Sales Certificate × ○ ○ - 5. Free Sales Certificate 5. Free Sales Certificate

Letter of Authorization × ○ ○ - 6. Letter of Authorization 6. Letter of Authorization

GMP certificate × ○ ○ - 7. GMP certificate 7. GMP certificate

(b) Product specifications

(a) History of development and

status of use in foreign

countries

2. Labelling and photo

9. IFU or Service manual

(d) Conformity assessment

(b) Product specifications

(e) Performance

(f) Risk management

(g) Manufacturing method

2. Labelling and photo

9. IFU or Service manual/ STED

-

8. Pre-clinical study/ STED8. Pre-clinical study

Special requirements for Class III

IVD/ STED

8. Pre-clinical study




8. Pre-clinical study/ STED



STED

Differences in requirement between Taiwan and Japan


Difference in requirements between high-class submission to Taiwan and Japan

Main reactive components

All raw materials

For Class III, all raw materials must be disclosed in the submission to TFDA whereas only main reactive components are submitted to PMDA.

Industry is reluctant to disclose unpatentable proprietary formulations even to authorities.


Difference in requirements between high-class submission to Taiwan and Japan

QC methods and CoA

Conducting release QC

During Class III review by TFDA, release QC is repeated using identical test specimens at designated laboratories in Taiwan and data is checked against submitted CoA.

Reducing redundancy would lessen workload of both Taiwanese authority and the manufacturers. Faster

product launch to deliver products to patients in need.


QMS Conformity Assessment at the time of application for marketing approval In addition to product examination, the marketing license holder for in vitro diagnostics and registered manufacturer of the products are investigated if they comply with QMS ordinance and establish the system to control manufacturing and quality.

QMS Periodical Conformity Assessment

The holder of marketing license for in vitro diagnostics and registered manufacturer of the product should be investigated for status of manufacturing and quality control according to the QMS every 5 years after obtaining approval.

4. QMS Conformity Assessment



Outline of QMS Conformity Assessment Case of conformity

Rationale for Issuance of Certificate of Conformity

4. QMS Conformity Assessment (Continued)

Certification

Product a Approval

Manufacture A

Product b Approval

Product c Certification

Manufacture B

Product d Approval

Certification Certification

Effective system !

Application for

assessment

On-site audit

or document

review

Assessment

report

Submission

of corrective

action plans

Certificate of

Conformity


Method comparison with predicates

Submission Guidance (1)

PMDA Approval IVD Reagents Sample size Quantitative test; 100 samples Qualitative test; positive =>50samples, negative=>50samples Criteria Quantitative test; correlation coefficient => 0.9 slope 0.9 – 1.1 (linear regression) Qualification test; concordance rate => 90% Notified Body Certification IVD Reagents Sample size Quantitative test; 50 samples Qualitative test; positive =>50samples, negative=>50samples Criteria Same as PMDA approval


Clinical Trial Protocol


Novel products Already available products but additional new clinical usage Test facilities => 2 facilities Sample size => 150 samples (including normal population interval) Consideration Targeted disease or pathologic condition Reference interval or Cut-off point Rationale for Cut-off Point (detection, qualitative test) Sensitivity true positive rate Specificity true negative rate


Preapproval Study


Novel products Already available products but additional new clinical usage Test facilities => 2 facilities Sample size => 150 samples (including normal population interval) Consideration Targeted disease or pathologic condition Reference interval or Cut-off point Rationale for Cut-off Point (detection, qualitative test) Sensitivity true positive rate Specificity true negative rate etc.


Key approaches 1. Improving the quality of review process

• Improvement of consultation system

• Improvement of application through educational opportunities given by industry associations

• Reorganization of PMDA review departments …and others

2. Setting standard of time to approval

• Set targets of time to approval by FY 2018

• Generic products (Me-too) ; 7months / Novel products; 13months

3. Increase reviewers

• Increase the number of reviewers to implement above mentioned improvement plans

4. Progress management

• These collaborative action plans shall be monitored and evaluated, and action plans may be revised.

Collaboration plan to quicker pre-market approval (FY2015 – 2018)

Aim: To quickly deliver effective IVD products to medical community in need, both the reviewers and the applicants work together to improve the quality of reviewing process and shorten the time to approval.


Improving consultation

Face-to-face consultation by PMDA and developer PMDA accepts consultation requests from developers at various stages of IVD product development.

Types of Consultation

• Preparatory consultation

• Pre-development consultation of IVD reagents

• Pre-development consultation of companion diagnostics (CDx)

• CDx Package development consultation

• Protocol consultation (Quality / Performance / Correlation / Clinical performance study / Clinical performance study of CDx)

• Evaluation consultation (Quality / Performance / Correlation / Clinical performance study / Clinical performance study of CDx)

• Application procedure consultation

• Additional consultation

• Simple consultation

• Simple consultation for certification criteria

• General consultation

Health


謝謝！

ご清聴ありがとうございました。

overview of licensing and product approval processes for ... · three pillars of product release to...

Documents