Dokumentvorlage für Diplomarbeiten

Medical Device Regulations in the People’s Republic of China -

the New Trend and the Challenges and Opportunities

to European Medical Device Manufacturers

Wissenschaftliche Prüfungsarbeit

zur Erlangung des Titels

„Master of Drug Regulatory Affairs“

der Mathematisch-Naturwissenschaftlichen Fakultät

der Rheinischen Friedrich-Wilhelms-Universität Bonn

vorgelegt von

Xinyu Meng

aus Jiangsu, China

Bonn 2019

Betreuer und 1. Referent: Dr. Ehrhard Anhalt

Zweiter Referent: Dr. Santiago Figueroa-Perez

TABLE OF CONTENTS

TABLE OF CONTENTS .................................................................................. I

List of Abbreviations ................................................................................... III

List of Tables............................................................................................... IV

List of Figures ............................................................................................. IV

1. Background ......................................................................................... 5

1.1 Aims and objectives .............................................................................. 6

1.2 Notes .................................................................................................... 6

2. Marketing Approval System for Medical Devices in China ............. 7

2.1 Qualification of the applicant ................................................................. 7

2.2 “Agent” of Imported Medical Devices .................................................... 7

2.3 Classification of Medical Devices ......................................................... 9

2.4 Registration Units ............................................................................... 11

2.5 Marketing Approval Certificates .......................................................... 12

2.6 Label and IFU ..................................................................................... 13

3. Application Procedures for Marketing Approvals of Imported

Medical Devices in China ................................................................. 15

3.1 Application Types ............................................................................... 15

3.2 Application procedures for approval of class II and class III imported

medical devices .................................................................................. 15

3.2.1 Approval procedures (flowchart) ......................................................... 16

3.2.2 Application timeline ............................................................................. 17

3.2.3 Application requirements .................................................................... 18

3.3 Filing of class I imported medical devices........................................... 21

4. Discussion ........................................................................................ 23

4.1 Possible challenges from the current medical device regulations in

China .................................................................................................. 23

4.1.1 The importance of “Agent” .................................................................. 23

4.1.2 Possible classification differences ...................................................... 24

4.1.3 Possible difference in registration unit ................................................ 24

4.1.4 Possible issues with the Chinese label and IFU ................................. 25

4.1.5 Triggers for an “initial registration” ...................................................... 25

4.1.6 Possible issues with the submission dossier ...................................... 25

TABLE OF CONTENTS

4.2 Recent changes indicating the new trend in Chinese medical device

regulations .......................................................................................... 32

4.2.1 Clinical trial exemption ........................................................................ 32

4.2.2 Proposed clinical evaluation exemption for class II medical devices .. 35

4.3 Alternative options to registration testing ............................................ 36

4.4 Post market surveillance being strengthened ..................................... 39

4.5 Overseas on-site audits to be conducted ............................................ 40

4.6 Special review procedure for innovative devices ................................ 42

5. Conclusion and outlook ................................................................... 45

6. Summary ........................................................................................... 48

Acknowledgement ...................................................................................... VI

References ................................................................................................. VII

List of Abbreviations

III

List of Abbreviations

AIMDD

Council Directive 90 / 385 / EEC of 20 June 1990 on the

approximation of the laws of the Member States relating to

active implantable medical devices

CAPA

Corrective and Preventive Action

CFDA

China Food and Drug Administration

CMDE

Centre for Medical Device Evaluation (China)

Ethics Committee

European Union

GCP

Good Clinical Practice

GHTF

Global Harmonization Task Force

GMP

Good Manufacturing Practice

ICH

International Council for Harmonisation of Technical

Requirements for Pharmaceuticals for Human Use

IEC

International Electrotechnical Commission

IFU

Instructions For Use

IMDRF

International Medical Device Regulators Forum

ISO

International Organization for Standardization

MDD

Council Directive 93 / 42 / EEC of 14 June 1993 concerning

medical devices

MDR

Regulation (EU) 2017 / 745 of the European Parliament and

of the Council of 5 April 2017 on medical devices

MAH

Marketing Approval Holder

NMPA

National Medical Products Administration (China)

PTR

Product Technical Requirement

QMS

Quality Management System

SAMR

State Administration for Market Regulation (China)

SFDA

State Food and Drug Administration (China)

United Kingdom

List of Tables

Table 1: Medical Device Classification (Body-contacting devices) ................. 9

Table 2: Medical Device Classification (Non-body-contacting devices) ........ 10

Table 3: Additional information in Chinese label and IFU ............................. 14

Table 4: Application Procedures ................................................................... 16

Table 5: Application timeline ......................................................................... 18

Table 6: Documentation for initial registration ............................................... 19

Table 7: Documentation for change application ............................................ 20

Table 8: Documentation for renewal application ........................................... 20

Table 9: Comparison between “agent” and “authorised representative” ....... 23

Table 10: Criteria of equivalency .................................................................. 29

Table 11: Discrepancies of requirements on the EC ..................................... 34

Table 12: Comparison of requirement on clinical evaluation......................... 35

Table 13: Comparison of requirements on submission dossier .................... 37

Table 14: Requirements on registration testing ............................................ 38

Table 15: Non-conformities to Chinese regulations ...................................... 42

Table 16: Requirement on marketing approval from the country of origin ..... 43

Table 17: List of important Chinese regulations ............................................ 46

Table 18: List of useful Chinese guidelines ................................................... 47

List of Figures

Figure 1: Marketing approval procedure ....................................................... 17

1. Background

With its large population, the People's Republic of China (will be abbreviated

as “China” in the rest of this thesis) is not an ignorable market to most foreign

medical device manufacturers, many of which are based in the EU. However,

having a marketing approval in the EU does not guarantee a marketing

approval in China. To many European manufacturers, the Chinese medical

device regulations are complex, challenging and ever-changing.

In March 2013 the former State Food and Drug Administration (SFDA) has

been reconstructed into the China Food and Drug Administration (CFDA),

subsequently the Chinese medical device regulations went through many

changes and the CFDA attempted to better normalize the review and

approval procedures for medical device applications. Since the new version

of the "Regulations for the Supervision and Administration of Medical

Devices"

[1]

and the "Provisions for Medical Device Registration"

[2]

came into

force in 2014, more new regulations and guidelines have been issued in

China, providing clarifications to critical issues such as the requirement on

clinical evaluations. Meanwhile, China actively participated in international

exchanges of medical device regulations. In 2013 China has become a full

member of the IMDRF

[3]

and in 2017 China has become a regular member of

the ICH

[4]

. As the approaches to reform the medical device approval system

in China, the CFDA issued the “Special Review Procedure of Innovative

Medical Devices (interim version)” in 2014

[5]

and in January 2018 finalized

the “Guideline on Accepting Foreign Clinical Data” within just 3 months after

the draft being published

[6] [7]

. Compared to the previously medical device

approval system that mainly based on local test data, such approaches

indicated positive signs that China is being more open to new medical

technologies. Additionally, many significant changes have been proposed in

the "Regulations for the Supervision and Administration of Medical Devices

(draft version)"

[8]

that have been submitted to the state council in November

2017, the proposals are currently under discussion.

In March 2018 the CFDA has been reconstructed into the National Medical

Products Administration (NMPA), which is now under the supervision of the

State Administration for Market Regulation (SAMR). New changes to the

medical devices regulations in China are to be expected. In August 2018 the

1. Background

SAMR issued the “Provisions for Adverse Events Surveillance and Re-

assessment of Medical Devices”

[9]

. The post market surveillance of medical

devices in China will be strengthened. In November 2018 the NMPA revised

and finalized the “Special Review Procedure of Innovative Medical Devices”

[10]

. The qualification of innovative devices has been further clarified and the

review procedure will be normalized.

1.1 Aims and objectives

The aim of this thesis is to provide a general but systematic review of the

current medical device regulations in China and analyse the gap between the

regulatory requirements in China and in the EU, with the focus on application

procedures for imported medical devices in China and the consideration of

possible challenges to be faced by European medical device manufacturers

that comply already with the medical devices regulations in the EU.

This thesis will also analyse the new trend in Chinese medical device

regulations and discuss the possible opportunities and challenges to be

brought to European medical device manufacturers.

1.2 Notes

Considering that many regulations (e.g., the classification system and

technical documentation requirements) of in vitro diagnostic devices are

significantly different from those of medical devices both in China and in the

EU, this thesis will not cover in vitro diagnostic devices.

Most of the Chinese regulations have been published in Chinese only. Some

of the articles and requirements quoted in this thesis have been translated

from the original Chinese texts into English by the author of this thesis. Notes

will be added when the quoted texts are translated from the original Chinese

texts.

2. Marketing Approval System for Medical Devices in China

2. Marketing Approval System for Medical Devices in

China

According to Article 2 and Article 5 of the “Provisions for Medical Device

Registration”, all medical devices sold and used in China shall apply for

registration or filing. Class I medical devices shall apply for filing (refer to

chapter 3.3); class II and class III medical devices shall apply for registration

(refer to chapter 3.2). For imported medical devices, the applications should

be submitted to the NMPA. A foreign applicant shall appoint an agent in

China to conduct the communication with the NMPA and activities defined by

corresponding regulations. According to Article 12 of the same “Provisions”,

the language of submission dossiers should be Chinese; regarding original

documents of foreign languages, both the original copy and translated

Chinese copy should be submitted.

2.1 Qualification of the applicant

As regulated by Article 6 and Article 9 of the “Provisions for Medical Device

Registration”, the registration applicant or filing entity brings the products to

the market in his own name and shall establish and maintain the quality

management system that covers the design and manufacture of the products

to be approved or filed in China. This requirement basically restricted the

registration applicant / filing entity to the “manufacturer” as defined by the

MDD and the MDR.

2.2 “Agent” of Imported Medical Devices

In China, the role of “Agent” of imported medical devices is similar to the role

of “Authorised Representative” in the EU. Both shall be responsible for the

communication between the manufacturer and the authority, and for post

market surveillance activities according to the corresponding regulations. The

name and address of the agent shall appear on the Chinese label and in the

Chinese IFU of imported medical devices in China, while the name and

address of the authorised representative shall appear on the label and in the

IFU of medical devices to be marketed in the EU.

Neither the MDD nor the AIMDD include detailed description of the role and

obligations of an authorised representative, giving the flexibility to define the

2. Marketing Approval System for Medical Devices in China

detailed responsibilities in the contract between the manufacturer and the

authorised representative. However more detailed requirements have been

included in the MDR. In China, even though the “Provisions for Medical

Device Registration” has already defined certain obligations of an agent, the

NMPA published a draft version of the “Provisions for the Supervision and

Administration of Agents of Imported Medical Devices”

[11]

in August 2018,

giving more detailed definition of the role and obligations of an agent.

According to this draft, the agent of imported medical devices shall have the

following obligations (note: translated into English by the author of this

master thesis):

 Apply for filing and registration according to corresponding regulations;

 Monitor and report adverse events from devices sold in China;

cooperate in event investigations;

 Conduct product recalls and report to authorities;

 Assist the authorities in investigating violations of Chinese regulations

by foreign “Marketing Approval Holders” (MAHs); (note: new

requirement)

 Cooperate in product sampling and evaluation of product quality and

provide information and data as requested by the authorities; (note:

new requirement)

 Maintain the traceability of devices sold in China and keep the

information of domestic marketing and distributions; (note: new

requirement)

 Communicate with authorities and foreign MAHs and inform the latter

about relevant regulations and technical requirements (also amended

ones) in timely manner;

 Assist foreign MAHs in completing the remaining tasks from

conditional approvals

; (note: new requirement)

 Take care of domestic complaints and inform foreign MAHs about

related information; (note: new requirement)

 Undertake joint responsibility for product quality and violation of

regulations.

Translated into “conditional approvals” by the author, because such certificates regularly

contain the wording “approved based on the following conditions …“.

2. Marketing Approval System for Medical Devices in China

2.3 Classification of Medical Devices

As defined by Table 1 and Table 2 below from the “Rules for Classification of

Medical Devices”

[12]

issued by the CFDA in 2015, medical devices are

classified into class I, II and III based on their risk levels.

Body-contacting device

Non-

active

device

Status of use

Patterns of use

Temporary use

(< 24 h)

Short-term use

(≥ 24 h; < 30 day)

Long-term use

(≥ 30 day)

Skin

/ Orifice

(openings)

Trauma

Tissue

Blood

circulation

/ Central

nerve

Skin

/ Orifice

(openings)

Trauma

Tissue

Blood

circulation

/ Central

nerve

Skin

/ Orifice

(openings)

Trauma

Tissue

Blood

circulation

/ Central

nerve

Liquid

transportation

device

Ⅱ

Ⅲ

Ⅱ

Ⅲ

Ⅱ

Ⅲ

Blood and other

body fluids

alternation

device

－

Ⅲ

－

Ⅲ

－

Ⅲ

Medical

dressing

Ⅰ

Ⅱ

Ⅰ

Ⅱ

－

Ⅲ

Invasive device

Ⅰ

Ⅱ

Ⅲ

Ⅱ

Ⅲ

－

Reusable

surgical device

Ⅰ

Ⅱ

－

Implantable

device

－

Ⅲ

Contraceptive

and family

planning device

(excluding

reusable

surgical device)

Ⅱ

Ⅲ

Ⅱ

Ⅲ

Other non-

active devices

Ⅰ

Ⅱ

Ⅲ

Ⅱ

Ⅲ

Ⅱ

Ⅲ

Active

Device

Status of use

Patterns of use

Minor injury

Moderate injury

Serious injury

Energy

treatment

device

Ⅱ

Ⅲ

Diagnostic and

monitoring

device

Ⅱ

Ⅲ

Liquid

transportation

device

Ⅱ

Ⅲ

Ionizing

radiation

device

Ⅱ

Ⅲ

Implantable

device

Ⅲ

Other active

devices

Ⅱ

Ⅲ

Notes: 1. “I”, “II” and “III” herein respectively refer to class I, II and III medical devices.

2. “-” herein means the situation is inapplicable to any class of medical devices.

Table 1: Medical Device Classification (Body-contacting devices)

2. Marketing Approval System for Medical Devices in China

Non-body-contacting device

Non-

active

device

Status of use

Patterns of use

little impact

Minor impact

Significant impact

Nursing device

Ⅰ

Ⅱ

－

Device for medical

device sterilization

and cleaning

－

Ⅱ

Ⅲ

Other non-active

devices

Ⅰ

Ⅱ

Ⅲ

Active

device

Status of use

Patterns of use

little impact

Minor impact

Significant impact

Clinical laboratory

instruments

Ⅰ

Ⅱ

Ⅲ

Stand-alone

software

－

Ⅱ

Ⅲ

Instruments for

medical devices

disinfection and

sterilization

－

Ⅱ

Ⅲ

Other active devices

Ⅰ

Ⅱ

Ⅲ

Notes: 1. “I”, “II” and “III” herein respectively refer to class I, II and III medical devices.

2. “-” herein means the situation is inapplicable to any class of medical devices.

Table 2: Medical Device Classification (Non-body-contacting devices)

However while in the EU medical devices are to be classified based on

certain general rules set out in Annex IX of the MDD or Annex VIII of the

MDR, in China the classification of a medical device has to be made in

accordance with the “Medical Device Classification Catalogue”

[13]

and a

product code shall be assigned to each medical device accordingly. The

above-mentioned catalogue will be updated from time to time and the current

version has been issued in 2017 by the CFDA. Compared to the previous

version, this new catalogue has expanded from 22 sub-catalogues to 43 sub-

catalogues and examples have been increased from 1008 to 6609, with the

addition of indication and description for each medical device and the

reclassification of medical devices from 40 categories into the lower class.

[14]

Finding the correct product code not only determines the product

classification but also helps identifying the applicable Chinese standards

correctly. In case there is no applicable category for the device to be

classified, the applicant can apply for the correct classification or submit

directly to the NMPA as a class III device (the NMPA will determine the

correct classification during the technical review).

2. Marketing Approval System for Medical Devices in China

2.4 Registration Units

It is very common that manufacturers combine different medical devices or

components for the clinical application as systems or procedure packs.

According to Article 12 of the MDD and Article 22 of the MDR, no extra CE

marking will be needed for systems or procedure packs if the requirements

have been met. This actually gives the flexibility in choosing different CE

marking approaches for the combination of medical devices or components,

either treating the combination as a device in its own right or applying for

conformity assessment for each component included individually.

In China, the applicant has less flexibility in defining a registration unit. In

2017 CFDA issued the “Guideline on Division of Registration Unit”

[15]

providing clarifications on the criteria for dividing different products and

components into separated applications. Incorrect defined registration unit

could result in the submission being rejected. According to the above-

mentioned guideline, the following rules should be considered (note:

translated into English by the author of this master thesis):

a) Active devices

 Devices of different technical principle should be submitted separately;

 Devices of different structure / component that affects product safety

and efficacy should be submitted separately;

 Devices of different performance criteria that leads to different

application scope or mechanism should be submitted separately;

 Devices of substantially different application scope should be

submitted separately;

 Active devices and the non-active consumables that have to be used

together should be submitted separately;

 Independent active devices to be used together in the same

application scope should be submitted separately;

 The main console and its applied parts should be submitted in the

same submission;

 Accessories with different intended use should be submitted

separately;

2. Marketing Approval System for Medical Devices in China

 Active accessories and non-active accessories that are regulated as

medical devices should be submitted separately unless they are

packed in the same sterile packaging.

b) Non-active devices

 Devices of different technical principles should be submitted

separately;

 Devices with and without drug / active ingredients should be submitted

separately;

 Devices of different surface treatments or structures that affect the

safety and efficacy should be submitted separately;

 Devices of different physical appearances that affect the safety and

efficacy should be submitted separately;

 Non-active devices and its active accessories should be submitted

separately;

 Devices of different structures/components or processed by different

procedures that affect the safety and efficacy should be submitted

separately;

 Single use and reusable devices should be submitted separately if the

difference affects the performance criteria;

 Devices treated by different sterilization processes should be

submitted separately if the difference affects the performance criteria;

 Devices of different structure that leads to different performance

criteria or different application scope should be submitted separately;

 Devices to be used in combination with different products that affects

the performance criteria should be submitted separately;

 Devices of different animal origins should be submitted separately;

 Devices of different application scopes should be submitted separately.

2.5 Marketing Approval Certificates

The registration certificates issued by the NMPA to class II and class III

imported medical devices are valid for 5 years and should have the

information listed below:

[16]

(note: translated into English by the author of this

master thesis)

 Certificate No.

 Name of the applicant

2. Marketing Approval System for Medical Devices in China

 Registered address of the applicant

 Address of the manufacturing site

 Name of the agent

 Registered address of the agent

 Product name

 Models and specifications

 Structure and components

 Application scope

 Attachment: Product Technical Requirement (PTR)

 Notes (in case of conditional approval)

 Issue date and expiry date

According to Article 49 of the “Provisions for Medical Device Registration”,

approval is requested for any change to the content on this certificate and its

attachment(s). Special attention should be paid to the attached PTR, which

will include technical specifications, testing criteria and testing methods of the

approved medical device. For each change in the PTR, even not being the

major change, a change application should be submitted. The importance of

PTR will also be discussed in later chapters of this thesis.

A change approval is a supplement to the initial certificate and is valid until

the expiry date of the initial certificate. It should have the information listed

below:

[16]

(note: translated into English by the author of this master thesis)

 Certificate No. (of initial certificate)

 Product name

 Change description (before and after change)

 Notes: this document is to be used with “xxxx” certificate

 Approval date

For class I medical devices, only an acceptance notice of the filing will be

issued, which has no expiry date.

[16]

2.6 Label and IFU

As regulated by the “Provisions for Instructions and Labels of Medical

Devices”

[17]

issued by the CFDA in 2014, the medical devices being sold and

2. Marketing Approval System for Medical Devices in China

used in China should be accompanied by the Chinese label and IFU.

However, the Chinese label and IFU should not be a simple translation of the

label and IFU used in the EU. Additional information has been requested by

the provisions mentioned above, in particular the following:

Additional information

Chinese

label

Chinese

IFU

Manufacturing site address (if applicable, the name and

address of contract manufacturer)

Name, address and contact information of the agent

Registration certificate number or filing number

PTR number

Manufacturing date, shelf life or expiry date

*Note: this is a mandatory section of the Chinese IFU; wordings like “please refer to the

label” should be included when it’s not practical to include the manufacturing date / expiry

date in the IFU.

Table 3: Additional information in Chinese label and IFU

3. Application Procedures for Marketing Approvals of Imported Medical Devices in China

3. Application Procedures for Marketing Approvals of

Imported Medical Devices in China

3.1 Application Types

For class I medical devices, filings should be submitted for initial record or for

changes of a filed record. No technical review will be involved.

[2]

For class II and class III medical devices to be marketed in China for the first

time, initial registration application should be submitted, and the approval will

be issued after the technical review for initial registration. For changes of

administrative information on the registration certificate or its attachments, a

filing should be submitted, and no technical review will be involved; for

changes to other approved items on the registration certificate or its

attachments, a change application should be submitted, and the approval will

be issued after the technical review for change application.

A renewal application should be submitted at least 6 months before the

expiry date of the certificate and the approval will be issued after the

technical review for renewal application.

[2]

For changes to approved IFUs of class II and class III medical devices, filings

should be submitted according to a specific IFU change procedure. A

rejection notice will be issued if the change should involve technical review,

in which case a change application should be submitted instead. If no

rejection notice has been issued within 20 working days after the acceptance

date, then the proposed IFU changes can be implemented.

[18]

For imported medical devices, all the above-mentioned filings or applications

should be submitted to the NMPA.

[2]

3.2 Application procedures for approval of class II and class III

imported medical devices

The CMDE website listed the following procedures that the applicant has to

take into consideration during the preparation of the application, the technical

review by the CMDE and the post market phase for class II and class III

imported devices.

[19]

3. Application Procedures for Marketing Approvals of Imported Medical Devices in China

Mandatory procedure

Optional procedure

Preparation phase

Pre-application consulting

Classification application

Type testing

Clinical evaluation

Innovation qualification

Technical review

phase

Acceptance of application

Priority qualification

Supplement request

Expert meeting

Rejection / Withdrawal

Approval

Post market phase

Change application

Renewal application

IFU change application

Table 4: Application Procedures

Type testing and clinical evaluation are both categorized as mandatory

procedure for applications in China, while in the EU type testing is not

mandatory but depends on which conformity assessment route the

manufacturer selects. The detailed requirements on type testing and clinical

evaluation will be discussed in chapter 4 of this thesis.

3.2.1 Approval procedures (flowchart)

According to the guidelines issued by the CFDA in 2017 on the initial

registration, the change application and the renewal application for class II

and class III imported medical devices

[20] [21] [22]

, the processes are similar

and can be summarized into the flowchart from Figure 1 below:

3. Application Procedures for Marketing Approvals of Imported Medical Devices in China

Figure 1: Marketing approval procedure

Notes:

1. Formal inspection to be conducted by the administrative service centre of the NMPA;

2. Decision of acceptance to be made by the administrative service centre of the NMPA;

3. Technical review to be conducted by the CMDE;

4. Only 1 chance of supplement submission (must be submitted within 1 year); only 3

face-to-face discussions with the reviewer will be allowed; only 1 chance of pre-

review before the supplement submission will be allowed.

3.2.2 Application timeline

The timelines for initial registration, change application and renewal

application in China can be summarized into Table 5 below:

Certificate

issued

Formal

inspection

Application

submitted

Application

accepted

Application

approved

Technical

review

Application

rejected

Application

re-submitted

Corrective

notice

Supplement

submission

Supplement

notice

Application

withdrawn

3. Application Procedures for Marketing Approvals of Imported Medical Devices in China

Procedure

Timeline

Formal inspection

5 working days

Transfer of documentation

3 working days

Technical review

Class II: 60 working days

Class III: 90 working days

Decision of approval

20 working days (+ 10 working days if necessary)

Issue of certificate

5 working days

Notes:

1. Clock stops on the issue date of supplement notice and re-starts on the reception

date of supplement submission

2. The above listed timeline does not include extra time for expert meetings and / or on-

site audit

Table 5: Application timeline

3.2.3 Application requirements

3.2.3.1 Initial registration of imported medical devices

For class II and class III imported medical devices to be marketed in China

for the first time, a dossier including the following sections listed in Table 6

below should be submitted for initial registration applications according to the

“Guideline on Initial Registration of Imported Medical Devices” issued by the

NMPA in 2018.

First level title

Second level title

1. Application form

2. Qualification files

3. Basic requirement list for the

safety and efficacy

4. Summary info

4.1 Overview

4.2 Product description

4.3 Models and specifications

4.4 Packaging description

4.5 Intended use and contraindications

4.6 Equivalent product or product of

previous generation (if applicable)

4.7 Others

5. Research data

5.1 Performance

5.2 Biocompatibility

5.3 Biological safety

3. Application Procedures for Marketing Approvals of Imported Medical Devices in China

5.4 Disinfection and sterilization process

5.5 Shelf life and packaging

5.6 Animal studies

5.7 Software

5.8 Others

6. Manufacturing info

6.1 Manufacturing process of non-active /

active devices

6.2 Manufacturing sites

7. Clinical evaluation

8. Product risk assessment

9. Product technical requirement

10. Registration test report

10.1 Test report

10.2 Pre-evaluation conclusion

11. IFU and labels

11.1 IFU

11.2 Label samples of units for sale

12. Declaration of conformity

Note: translated into English by the author of this master thesis.

Table 6: Documentation for initial registration

3.2.3.2 Change application

As regulated by Article 49 of the “Provisions for Medical Device Registration”,

in China, applications should be submitted for all changes to the initial

registration certificate and related attachments. For changes to administrative

information, a filing should be submitted; for other changes, a change

application for approval should be submitted.

According to the “Guideline on Change Application of Imported Medical

Devices”

issued by the NMPA in 2018, a dossier including the following

sections listed in Table 7 below should be submitted for change applications

of class II and class III imported medical devices.

Section

Notes

1. Application form

2. Qualification files

3. Declaration on changes

4. Copy of initial approval

certificate and previous change

approvals

5. Descriptions of changes

Change comparison form and explanations

3. Application Procedures for Marketing Approvals of Imported Medical Devices in China

on the following items, if applicable:

- product name;

- product technical requirement;

- model and specifications;

- structure and components;

- intended use;

- on manufacturing site address;

- on other content in the certificate;

- on other changes

6. Risk management report

regarding the changes

7. Evaluation on changes to the

safety and efficacy

*Clinical evaluation is a must for changes

to intended use.

8. Registration test report

regarding changes to the PTR

9. Declaration of conformity

- Conformity to Chinese regulations and

standards, with a list of applicable

Chinese standards;

- Self-declaration on truthfulness

Note: translated into English by the author of this master thesis.

Table 7: Documentation for change application

3.2.3.3 Renewal application

According to the “Guideline on Renewal Application of Imported Medical

Devices”

[22]

issued by the NMPA in 2018, a dossier including the following

sections listed in Table 8 below should be submitted for the renewal of

existing marketing approval of class II and class III imported medical devices.

Section

Notes

1. Application form

2. Qualification files

3. Declaration on no change

*no change to the most recent

approval (initial or change

approval)

4. Copy of initial approval certificate and

previous change approvals

5. Summary and related documentation on

the remaining tasks required by

conditional approval.

*the previously requested

summary report on post

marketing surveillance has been

exempt in the 2018 revision

issued by NMPA

[18]

Note: translated into English by the author of this master thesis.

Table 8: Documentation for renewal application

3. Application Procedures for Marketing Approvals of Imported Medical Devices in China

Since the issue of the “Provisions for Medical Device Registration” in 2014,

the CFDA offered to simplify the procedure of renewal application and

accelerate the technical review. To achieve such simplification and

acceleration, the renewal application has been restricted to the “non-change

renewal application” and has to be submitted separately from change

applications

[16] [22]

. The previous approach of combining the renewal and

change applications together are no longer allowed. In 2018 the NMPA

revised again the documentation requirement for renewal applications

[27]

further simplifying the documentation for renewal submissions. This is to

align with the new “Provisions for Adverse Events Surveillance and Re-

assessment of Medical Devices”, which requires the MAH to submit

periodically a summary of adverse events, surveillance data, risk assessment

and management to the responsible authorities.

Although the documentation for renewal submission has been simplified, it

doesn’t mean technical review will be omitted. According to Article 55 of the

“Provisions for Medical Device Registration”, the renewal application shall not

be approved if the most recent version of applicable Chinese standards

cannot be met or the tasks listed on the initial registration certificate have not

been completed. Hence it is still possible that additional tests and data being

requested to get the initial certificate renewed. The applicant should review

the up-to-date status of the Chinese standards being referred to and identify

if any new Chinese standards not being referred to could be applicable as

well.

3.3 Filing of class I imported medical devices

The filing of class I imported medical devices should be submitted to the

NMPA. The administrative service centre of the NMPA will check the format

and completeness of the filing dossier. If it complies with the required format,

a notification on acceptation of the filing dossier will be issued upon reception.

According to Article 9 of the current “Regulations for the Supervision and

Administration of Medical Devices”, the following documentation should be

submitted for the filing of class I medical devices (note: translated into

English by the author of this master thesis):

 risk assessment documentation;

3. Application Procedures for Marketing Approvals of Imported Medical Devices in China

 product technical requirement;

 product test report;

 clinical evaluation documentation;

 product IFU and label sample;

 quality system documentation related to product development and

manufacture;

 other data to demonstrate the product safety and efficacy.

4. Discussion

4.1 Possible challenges from the current medical device regulations in

China

4.1.1 The importance of “Agent”

Chapter 2.2 introduced the role of “Agent” in China and its obligations. To

further discuss the similarity and differences between the role of “Agent” in

China and the role of “Authorised Representative” in the EU, Table 9 below

summarizes the major obligations of these two roles as defined by

corresponding regulations. It is worth noting that both in China and in the EU

the trend is to better supervise the local agent / representative.

Agent in China

Authorised

Representative in the EU

Role and obligations

Current

provisions

Planned

provision

(draft)

MDD /

AIMDD

MDR

The sole representative

Communication between

the authority and the

manufacturer

Establish a quality

management system

Submit the application

for filing or registration

Provide to the authority

the evidences of

regulatory compliance

Post market surveillance

and vigilance activities

Note: x = covered; xx = strengthened

Table 9: Comparison between “agent” and “authorised representative”

The contract between the agent and the foreign applicant is not the subject of

review by the NMPA. It is the responsibility of both the applicant and the

agent to make sure that the contract covers the requested obligations

completely. In each application the agent shall submit to the NMPA a

declaration on fulfilling all the obligations defined by regulations in China.

4. Discussion

4.1.2 Possible classification differences

The medical device classification rules in China have been explained in

chapter 2.3. The most significant difference between the classification rules is

that in China the intended duration of use has been divided into “temporary”

(< 24 h), “short-term” (≥ 24 h; < 30 day) and “long-term” (≥ 30 day), while

both the MDD and MDR divide the duration into “transient” (< 60 min), “short-

term” (≥ 60 min; ≤ 30 day) and “long-term” (> 30 day). Due to this difference,

the “short-term” devices in the EU that claim to be used for at least 60

minutes but less than 24 hours will be defined as “temporary” devices in

China and possibly classified into a lower class than in the EU.

Certain special rules from the same classification rules mentioned above will

also cause discrepancies, such as:

 A medical device supplied in sterile state shall always be classified as

class II or above;

 A medical device with measuring function shall always be classified as

class II or above.

Because technical review by the CMDE is mandatory for class II and class III

imported medical devices, if a class I device in the EU has been classified

into higher class in China, it is possible that the CMDE will review extra data

and information that have never been requested by the notified bodies.

4.1.3 Possible difference in registration unit

According to the rules described in chapter 2.4 for defining a registration unit

for medical device submissions in China, it is possible that the compilation of

a system / procedure pack (the registration unit) in China has to be defined

differently from the approved system / procedure pack in the EU. According

to Article 12 of the MDD, the entity that puts the system / procedure pack on

the European market does not have to be the “manufacturer” of the system /

procedure pack. However as explained already in chapter 2.1, in China the

registration applicant or filing entity has to be the manufacturer of the

registration unit. Hence it will cause issues if the applicant does not have the

quality management system that covers the design and manufacture of the

whole system / procedure pack (registration unit) to be approved or filed in

China.

4. Discussion

4.1.4 Possible issues with the Chinese label and IFU

Chapter 2.6 summarized the additional requirements on the Chinese label

and IFU. It is worth noting that according to section 13.1 in Annex I of the

MDD and section 23.1 (d) in Chapter III of the MDR, instructions for use shall

not be required for class I and class IIa devices if such devices can be used

safely without any such instructions. However, in China, no such exemption

has been included in the provisions mentioned above.

It is also worth noting that although the Chinese label and IFU of medical

devices are also subject to review by the NMPA, they are not issued as

attachments of the approval certificate for medical devices. According to

Article 49 of the “Provisions for Medical Device Registration”, only changes to

the certificate and related attachments are subject of review and approval by

the NMPA. For changes to the approved Chinese IFU of class II and class III

devices, according to the “Filing Procedure of Changes to Medical Device

IFUs”

[18]

published in 2015, a filling should be submitted to the NMPA, as

explained in chapter 3.1.

4.1.5 Triggers for an “initial registration”

Chapter 3.2.3.1 deals with the documentation to be submitted for an “initially

registration” of class II and class III medical devices in China. Such an “initial

registration” literally applies to any device that has never been marketed in

China before. However, based on the experiences from the author of this

thesis, the NMPA may request the applicant to submit an “initial registration”

if the proposed changes of the approved medical device are considered by

the NMPA as significant. Additionally, if the renewal application for the

existing certificate has not been submitted and accepted by the NMPA within

the regulated deadline, an “initial registration” shall be submitted instead.

Chapter 4.1.6.2 will further discuss when a change application could trigger

an initial registration submission.

4.1.6 Possible issues with the submission dossier

4.1.6.1 Initial registration

The general structure and requirements of the initial registration submission

dossier of class II and class III medical devices in China share a lot of

4. Discussion

common features with the GHTF document “Summary Technical

Documentation for Demonstrating Conformity to the Essential Principles of

Safety and Performance of Medical Devices (STED)”

[23]

. Considering that the

technical documentation in accordance with the MDD or the MDR also

shares a lot of common features with the STED, the existing data generated

for the technical documentation for CE approval should be able to cover a

major part of the submission dossier for initial applications in China.

Special attention should be paid to the following sections, which would

require additional data in comparison to the technical documentation of a CE

marked device or otherwise cause discrepancies:

A) Product Technical Requirement (PTR)

As requested by Article 15 of the “Provisions for Medical Device

Registration”, for class II and class III medical devices, the PTR should

be submitted for approval, and the devices being marketed in China

should comply with the approved PTR.

According to the “Guideline on drafting Product Technical

Requirement”

[24]

issued by the CFDA, the PTR should include the

following content: (note: translated into English by the author of this

master thesis)

1) Product name;

2) Product models / specifications and descriptions of all the

differences between them;

3) Performance criteria related to the function, safety and quality

control of the finished product; the criteria should at least meet the

requirements from applicable mandatory Chinese national and

industrial standards.

4) Testing method to verify that the finished product can meet the

criteria.

The PTR is a China specific document. It includes crucial information

from product design as well as necessary quality control measures. It

is crucial for medical device approvals in China not only as an

important attachment to the registration certificate that defines the

product models / specifications and performance criteria, but also as

4. Discussion

the link between the product design, quality control and Chinese

standards.

It is worth noting that the Chinese standards will be updated

periodically, and the PTR should always take reference to the latest

version of Chinese standards. It is actually similar to the reference of

latest harmonized standards in the technical documentation for CE

approval. Although many Chinese standards are actually adopted from

harmonized standards such as ISO and IEC standards, discrepancies

and different interpretations do exist. It is also very common that the

most recent Chinese standard is adopted from an obsolete version of

the equivalent harmonized standard because the adoption will take

time. Hence when referring to Chinese standards in the PTR, it is

necessary to evaluate the possible discrepancies between the

requirements in China and in the EU.

B) Registration test report

Chinese test institutions conduct type testing for different purposes.

Type testing for registration purpose is conducted in accordance with

the PTR proposed by the applicant and reviewed by the test institution.

It has to be a full test with test samples manufactured in the controlled

quality management system.

In the EU, type testing is not always necessary to get market

approvals depending on the conformity assessment route selected by

the manufacturer. However, in China, the registration test report

issued by a qualified Chinese test institution is mandatory and the pre-

evaluation conclusion from the same test institution has to be

submitted as well for initial applications according to the current

“Provisions for Medical Device Registration”.

C) Clinical evaluation, clinical trial

According to Article 22 of the current “Provisions for Medical Device

Registration”, clinical trial has to be conducted for all class II and class

III medical devices, unless the product is on the exemption list or it

applies one of the following criteria:

4. Discussion

1) Where the functional mechanism of the device is definite, the

design is finalized, the production process is well-established, and

an equivalent marketed medical device has been in clinical use for

years and no serious adverse events are recorded, and its

conventional purposes of use are not changed;

2) Where safety and effectiveness of the device can be proved

through non-clinical evaluation;

3) Where safety and effectiveness of the medical device can be

demonstrated through the analysis and assessment made on the

basis of the data obtained from clinical trial or application of an

equivalent medical device.

Even though the above listed alternative approaches have been

allowed, the criteria of equivalency have not been clarified. In April

2015 the CMDE issued the “Guideline on the Clinical Evaluation of

Medical Devices”

[25]

, which for the first time elucidated the criteria of

equivalency and the requirements on different approaches for clinical

evaluation. In summary, three different acceptable approaches have

been explained in this guideline:

1) Exempted device – the (imported) product is equivalent to an

approved device in China of the same exempted category;

2) Non-exempted device – but (imported) product is equivalent to an

approved device in China;

3) Clinical trial.

The equivalency on items listed in Table 10 below should be taken

into consideration.

Equivalency on

Equivalency to

exempted

device

non-exempted device

(non-active device)

non-exempted device

(active device)

Working principle

Structure

Manufacturing

procedure

Production

materials

(especially

human

contacting

materials)

(including material

brand, animal source

material, allogeneic

material, components,

drug components,

biologically active

(including material

brand, animal source

material, allogeneic

material, components,

drug components,

biologically active

4. Discussion

material, applicable

standards)

material, applicable

standards)

Performance

requirements

(performance

parameters; function

parameters)

Safety evaluation

(including

biocompatibility,

biological safety, etc.)

(including

biocompatibility,

biological safety, EMC,

etc.)

Core function of

software

Applicable

national /

industrial

standards

Intended use

(including intended

population, application

areas, human contact

type, indications,

disease stage and

extend of indications,

application

environment)

(including intended

population, application

areas, human contact

type, indications,

disease stage and

extend of indications,

application

environment)

Method/Type of

application

Contraindication

Caution and

warnings

Sterilization

Packaging

Labelling

Instructions for

Use

Delivery status

Table 10: Criteria of equivalency

As the table above shows already, to demonstrate the equivalency,

the applicant has to provide for both the reference and new device the

detailed information that is not publicly available, such as production

materials, manufacturing procedure and applicable standards. In

addition, when choosing the equivalency approach, a clinical

evaluation report (CER) has to be provided as the alternative

4. Discussion

document to the clinical trial report. The CER should also include the

following, not publicly available information (note: translated into

English by the author of this master thesis):

1) Non-clinical research data;

2) Literatures;

3) Clinical application experience data;

4) Complaints and adverse events;

5) CAPAs related to clinical risks;

6) Data from Chinese population;

7) Additional clinical study in China.

Due to restrictions from the availability of requested information and

data from reference devices, it’s not practical to choose the

equivalency route when only similar products from competitors have

been approved in China. It makes more sense to choose this

approach when the same applicant has similar products or same

products of previous generation that have been approved in China

already. However, the significance of differences still has to be

determined during the case-by-case review. In case of insufficient data,

it would be very challenging to finish the additional clinical study within

the 1-year deadline for supplement submission as restricted by Article

35 of the “Provisions for Medical Device Registration”. The worst case

could be withdrawal of the application due to insufficient data.

If the equivalency approach is not feasible, then clinical trial has to be

conducted for class II and class III medical devices. However, in the

EU, if the device is neither implantable nor in Class III, clinical trial is

not always the first option to demonstrate its safety and efficacy.

According to Article 23 of the “Provisions for Medical Device

Registration”, the clinical trial institution should be qualified in

accordance with the Chinese “Good Clinical Practice”, meaning only

clinical trial data from qualified Chinese institutions would be accepted.

In 2018 the CFDA issued the final version of the “Guideline on

Accepting Foreign Clinical Data”, offering to simplify the application

procedure for applicants with qualified non-local clinical trial data.

4. Discussion

Chapter 4.2.1.1 of this thesis will further discuss the meaning and

impact of this guideline.

4.1.6.2 Change application

Chapter 3.2.3.2 introduced the requirements for change applications for class

II and class III medical devices in China. Although no explanation has been

given in the “Provisions for Medical Device Registration”, not all changes can

be approved through change applications. The “Guideline on Division of

Registration Unit”

should be taken into consideration when deciding whether

the proposed changes may trigger a new application (= initial registration) in

China. The key criteria will be the significance of differences between the

technical principle, structure / component, performance criteria and

application scope. However, whether the changes are significant enough to

trigger a new application, interpretations from the applicant, the

administrative service centre of the NMPA and different reviewers from the

CMDE could be different. It is possible that an accepted change application

being rejected during the technical review and a new application for the

changed product has to be submitted instead.

In the EU, the manufacturer can always consult the notified body on the

necessity of a change notification or the application for a new certificate. In

China however, although the NMPA offers pre-submission consultation to

applicants, the communication will be much more limited than that between

the manufacturer and the notified body in the EU. As explained in the CFDA

announcement on the implementation of pre-submission consultation

[26]

, only

very few appointments will be scheduled, and the applicant has to apply for

an appointment far in advance. Also, the duration of consultation will be very

short and only up to 5 questions are allowed to be posted by an applicant in

each consultation. Furthermore, different offices from the CMDE will attend

the consultation in rotation and only questions related to the responsibilities

of the attending office can be asked during the consultation.

Considering the

uncertainties, it is recommendable to conduct the case-by-case assessment

of the impact from proposed changes to existing approvals in China.

Regarding the dossier requirement, special attention should still be paid to

the possible involvement of registration test and clinical evaluation. The

4. Discussion

necessity of additional tests to be done in China should be evaluated

thoroughly before the submission because it would be very difficult to finish

them later within the 1-year deadline of supplement submission.

4.2 Recent changes indicating the new trend in Chinese medical

device regulations

The publication of the “Provisions for Medical Device Registration”

in 2014

has been followed by the publication of many other new regulations and

revisions to existing regulations in China, some of which indicated very

intriguing new trend. This chapter will discuss the most significant new

changes in Chinese medical device regulations.

4.2.1 Clinical trial exemption

4.2.1.1 The acceptance of foreign clinical trial data

As mentioned already in section 4.1.6.1 of this thesis, clinical trial is a must

for all class II and class III medical devices unless meeting the criteria of

exemption according to the current “Provisions for Medical Device

Registration”. However, it is difficult to get such exemptions, i.e., to obtain all

the requested information to demonstrate the equivalency to devices that

have been approved in China already. Hence the publication of the

“Guideline on Accepting Foreign Clinical Data” is definitely good news to

foreign applicants because due to the qualification of clinical trial institution,

local clinical trial data will be necessary for imported class II and class III

medical devices that cannot be exempted from clinical trials. However, this

new guideline will not put an end to the need of local clinical trial data for

imported class II and class III medical devices, but rather provides an

alternative choice for those applicants with qualified existing data.

First of all, the data covered in this guideline should meet the following

criteria (note: translated into English by the author of this master thesis):

 clinical trial data to assess the product safety and efficacy under

normal use condition

 obtained from qualified clinical institutions

 for the same device that applies for approval in China

4. Discussion

Secondly the data should be obtained following the basic requirements listed

below:

 in accordance with the Helsinki Declaration;

 in accordance with the Chinese “Good Clinical Practice for Medical

Devices”

[28]

(any discrepancy should be justified);

 the applicant and clinical trial institution should be the subject of

supervision and inspection from the NMPA;

 the data obtained should be truthful, reliable and traceable and the

complete data should be provided to the NMPA.

The data to be submitted to the NMPA should include at least the clinical trial

protocol, conclusion from the ethic committee and complete clinical trial

report with the analysis of the complete data and its conclusion.

If applicable Chinese guidelines on the same or similar product category

include requirements on the clinical trial such as trial design, sample size and

endpoints, the foreign data have to meet these Chinese requirements. And in

case of discrepancies that cannot be justified, additional clinical study in

China will be requested. The differences between factors such as races,

living conditions and medical facilities that may affect the clinical trial result

should also be taken into consideration and should be justified.

4.2.1.2 The challenges and opportunities

While providing an alternative approach to conducting local clinical trials in

China, the data that may be accepted will be restricted to data with good

quality from a full-scale clinical trial. However, in the EU, a full-scale clinical

trial is not always the first option for medical device manufacturers. Hence

this new guideline will not be helpful to manufacturers that have never

conducted a full-scale clinical trial. Additionally, the MDD doesn’t require the

clinical investigations for medical devices to be conducted in accordance with

the GCP. Although the MDR now requires that clinical investigations for

medical devices should be in line with the international standard ISO

14155:2011

( 2 )

on good clinical practice, it should be noted that ISO

14155:2011 does not cover many aspects that have been required by the

(2)

ISO 14155:2011, Clinical investigation of medical devices for human subjects -- Good

clinical practice.

4. Discussion

GCP that were primarily developed for clinical trials of medicinal products. It

is also worth noting that although the Chinese GCP takes reference from the

ICH Guideline on Good Clinical Practice

[29]

, there are noticeable

discrepancies aside from Chinese local laws and regulations. As an example,

Table 11 shows the discrepancies of requirements on the ethics committee

(EC) between the Chinese GCP, the ICH Guideline and ISO 14155:2011.

Chinese GCP

ICH Guideline on GCP

ISO

standard

14155:2011

Composition

of the EC

- At least five members,

including members from

medical and non-medical

area and members of

different gender;

- At least one member of

legal occupation among

members from non-

medical area.

- At least one member who

is independent of the

institution / trial site.

(a) At least five members.

(b) At least one member

whose primary area of

interest is in a non-

scientific area.

is independent of the

institution / trial site.

N / A

Document

retention

The EC should retain all

relevant records for a

period of at least 10-years

after completion of the trial.

The EC should retain all

relevant records for a period

of at least 3-years after

completion of the trial.

N / A

Table 11: Discrepancies of requirements on the EC

Despite discrepancies, both China and the EU have been trying to harmonize

the clinical trial requirements with international regulations. And since the

CFDA became the regular member of ICH in 2017, the harmonization

procedure in China has been accelerated. The publication of the “Guideline

on Accepting Foreign Clinical Data” is CFDA’s first attempt to save

unnecessary cost, time and effort for applicants who have already obtained

solid data in compliance with recognized international regulations.

The applicant should carefully review the existing clinical trial data and

analyse possible gaps between the relevant requirements in China and in the

EU. If discrepancies cannot be fully justified, additional clinical study in China

should be taken into consideration. CFDA recommended that the applicant

should consult CFDA’s reviewer first before submitting registration

applications with foreign clinical trial data only. Considering the 1-year

deadline for the supplement submission, it would make sense to do some

4. Discussion

pre-preparation works for possible additional clinical study in China before

the submission, such as screening potential clinical study site(s), planning for

budget and resource. In case additional clinical data have been requested

during the review, the applicant should make full use of the very limited

chances to discuss with the reviewer on the design and sample size of the

clinical study and possible extension of the review time.

Now that the MDR also requires higher quality for clinical data, if planned in

advance and covering the specific requirements from Chinese GCP in the

clinical investigation protocol, there could be good chance of using the same

clinical data for both the conformity assessment in the EU and the

registration application in China.

4.2.2 Proposed clinical evaluation exemption for class II medical devices

In November 2017 the "Regulations for the Supervision and Administration of

Medical Devices (draft version)" has been submitted to the state council of

China. This draft version included many proposed revisions to the current

“Regulations for the Supervision and Administration of Medical Devices”.

One

significant revision is to the requirement on clinical evaluation. Table 12

compares the relevant articles in the current version and the proposed

version of the above-mentioned regulations and in the current version of

“Provisions for Medical Device Registration” (note: translated into English by

the author of this master thesis).

"Regulations for the Supervision and Administration

of Medical Devices"

“Provisions for

Medical Device

Registration”

(2014)

Proposed version (2017)

Current version

(2014)

Article 17:

… For application for registration

of a class II medical device,

clinical evaluation is not

mandatory; For application for

registration of a class III medical

device, clinical evaluation is

mandatory …

Article 19:

… For application for

registration of a class

II or class III medical

device, clinical trial

shall be conducted…

Article 22:

… For application for

registration of a class

II or class III medical

device, clinical trial

shall be conducted…

Table 12: Comparison of requirement on clinical evaluation

4. Discussion

Due to some of the proposed revisions being very significant, the discussion

on this new "Regulations for the Supervision and Administration of Medical

Devices" is expected to take quite some time and there is no guarantee that

all of the proposed revisions will be approved by the state council. However,

this proposal indicated intriguing signs already. Firstly, clinical trial will no

longer be the first option to apply for a registration certificate in China;

compared to previously restricting to clinical trial only, the NMPA is now

trying to accept alternative clinical evaluation approaches. Secondly, the

NMPA is trying to further simplify the application procedure for class II

devices; in addition to reducing the unnecessary cost, time and effort the

applicants have to invest during the preparation phase, this could also lead to

shorter review time for class II devices. Such positive attitude from the NMPA

is definitely good news to all applicants, and especially to manufacturers of

class II medical devices.

4.3 Alternative options to registration testing

The 2017 proposal of "Regulations for the Supervision and Administration of

Medical Devices (draft version)" also includes the revisions to the

documentation requirements on the submission dossier, in particular on the

requirement of product test report (investigation of product’s characteristics

versus corresponding standards) and clinical evaluation. Table 13 shows the

differences between the proposed version and the current version (note:

translated into English by the author of this master thesis).

"Regulations for the Supervision and Administration of Medical Devices"

Current version (2014)

Proposed version (2017)

Article 9:

The following documentation should be

submitted for the filing of class I medical

devices and the registration application

of class II and class III medical devices:

1) risk analysis documentation;

2) product technical requirement;

3) product test report;

4) clinical evaluation

documentation;

5) product IFU and label sample;

6) quality system documentation

Article 9:

The following documentation should be

submitted for the filing of class I medical

devices and the registration application

of class II and class III medical devices:

1) risk analysis documentation;

2) product technical requirement;

3) product test report;

4) product IFU and label sample;

5) quality system documentation

related to product development and

manufacture;

4. Discussion

related to product development and

manufacture;

7) other data to demonstrate the

product safety and efficacy.

The applicant is responsible for the

truthfulness of the submitted

documentation.

6) other data to demonstrate the

product safety and efficacy.

The product test report may be the

contract testing report from a qualified

test institution or self-testing report

from the applicant or filing entity.

For applications of class II and class III

medical devices that require clinical

evaluation, the clinical evaluation report

should be submitted.

The applicant is responsible for the

truthfulness, completeness and

traceability of the submitted

documentation.

Article 10

For class I medical devices, the product

test report can be self-testing report from

the applicant or filing entity; the clinical

evaluation documentation does not

require clinical trial report…

…

Article 10

(integrated into Article 9)

…

Article 11

…

For class II and class III medical devices,

the product test report should be

registration testing report from a qualified

test institution; the clinical evaluation

documentation should include clinical

trial report unless exempted.

Article 11

…

(integrated into Article 9)

Table 13: Comparison of requirements on submission dossier

The revision on the requirements of clinical evaluation is in line with the

proposed exemption of clinical trial for class II devices and further simplifies

the documentation.

The seemingly simplification on the requirements of the registration test does

not necessarily mean the exemption of registration testing. Table 14 shows

the requirements on registration testing from both the replaced version and

current version of the "Provisions for Medical Device Registration" (note:

translated into English by the author of this master thesis).

4. Discussion

"Provisions for Medical Device Registration"

Replaced version (2004)

Current version (2014)

Article 9

Class II and class III medical devices

have to complete registration testing

conducted by the test institutions

qualified by both the State Food and

Drug Administration and the General

Administration of Quality Supervision,

Inspection and Quarantine of the

People's Republic of China.

Clinical trials or registration application

can be carried out only after the

registration testing confirmed that the

product complies with the product

standard.

A list of qualified institutions will be

published separately.

Article 16

When applying for class II and class III

medical device registration, registration

testing shall be conducted. The medical

device testing institutions shall carry out

relevant registration testing on the

products in accordance with the product

technical requirements.

The production of samples for

registration testing shall comply with

relevant requirements of quality

management system for medical

devices. Clinical trials or registration

application can be carried out only after

the products passed the registration

testing.

For the filing of class I medical device,

the filing entity may submit the product

self-testing report.

Article 18

Medical device testing institutions shall

have the relevant qualification of medical

device testing, and perform testing within

their specified testing scope. It shall

carry out pre-evaluation of the product

technical requirements. The pre-

evaluation opinions together with the

medical device registration testing report

shall be issued to the applicant.

For the medical devices having not

included in the testing scope of any

medical device testing institutions, the

corresponding registration department

shall designate a testing institution which

has the capability to conduct the testing.

Table 14: Requirements on registration testing

Considering that the registration test report has always been the crucial and

mandatory document for medical device applications in China, and the test

institutions have to be qualified by the authorities, it is in the opinion of the

4. Discussion

author of this master thesis very unlikely that self-testing reports can be used

to replace the registration testing report for class II and class III medical

device applications. Additionally, the test institution that conducts the

registration testing plays the very important role as the pre-reviewers of the

PTR (replaced the previous product standard) as designated by the

regulations. The pre-evaluation should cover the following aspects (note:

translated into English by the author of this thesis):

[30]

 the completeness and applicability of the performance criteria; the

feasibility, repeatability and the suitability of the testing method;

 the completeness and applicability of the mandatory national standard

and industrial standard and the suitability of the clauses being referred

to;

 the feasibility, repeatability and the suitability of the referenced content

from the China Pharmacopeia.

As the pre-evaluation should cover many China specific requirements, in

case of self-testing reports, especially done by foreign manufacturers, there

could be issues with the acceptability of the PTR.

Since April 2017 the registration testing fee has been cancelled

[31]

, leading to

long waiting time for registration testing procedures and delay of applications.

This issue has been noticed by the CFDA already, stating that contract

testing report will also be accepted for registration purpose, as long as the

test has been conducted in accordance with the PTR and a pre-evaluation

conclusion from the test lab has been included.

[32]

Considering that both the

registration test and contract test are type testing conducted by qualified test

institutions, and the pre-evaluation conclusion from the test lab is still a

mandatory document for submissions in China, the proposed revision on the

registration test requirement could be the attempt from the NMPA to accept

other form of type testing for registration applications, rather than the sign of

exempting type testing in China.

4.4 Post market surveillance being strengthened

According to Article 5 of the “Provisions for Adverse Events Surveillance and

Re-assessment of Medical Devices”, the NMPA will establish a national

surveillance system for adverse events of medical devices. Article 14 of the

same “Provisions” requires the applicant to establish a quality management

4. Discussion

system that includes adverse events surveillance and product re-assessment;

the adverse events should be collected and reported in time and the product

risk evaluation report should be updated periodically based on surveillance

data. The trend of strengthening on medical device surveillance in China is in

line with the trend in the EU. However, it is worth noting that adverse events

occurred both within and outside China are required to be reported to the

NMPA for imported devices. Therefore, if the products are being marketed

both in China and in the EU, it would make sense to cover the new specific

requirements in China when updating the post market surveillance system to

meet the new MDR requirement.

Requirements for the “Marketing Approval Holders” (MAHs) of imported

medical devices to report adverse events occurred outside China:

 Serious adverse events leading to the product being controlled should

be reported to the NMPA within 24 h after the applicant being informed;

 Serious adverse events that may lead to serious injury or death of the

patient should be reported to the NMPA within 30 days after the

applicant being informed.

Additionally, the MAHs of imported medical devices should submit a

periodical risk evaluation report to the NMPA according to the regulations,

which should summarize and analyse the adverse events and surveillance

data from both within and outside China to re-evaluate the risk and benefit of

the product and record the risk control measures being taken.

According to the “Provisions for Recalls of Medical Devices”

[33]

the MAHs of

imported medical devices should report recalls conducted outside China to

the NMPA as well.

4.5 Overseas on-site audits to be conducted

Since December 2015 the CFDA started the implementation of overseas on-

site audits. Reports from the 24 overseas on-site audits conducted in 2017

have been published by the CFDA on its website. According to the NMPA, 26

overseas on-site audits have been conducted in 2018 and all the audit

reports will be published on its website. So far, 5 reports from the overseas

on-site audits conducted in 2018 have been published already.

[34]

4. Discussion

In China, the harmonized standard ISO 13485:2016

(3)

has been adapted into

a recommended industrial standard YY / T 0287-2017

( 4 )

and is not

mandatory. The mandatory QMS regulation in China and the basis for

overseas on-site audit is the “Good Manufacture Practice for Medical Devices”

[35]

(including its annexes

[36]

[37]

[38]

when applicable), covering the design,

manufacture, sales and after sale services of medical devices to be and

being marketed in China. In general, the “Good Manufacture Practice for

Medical Devices” has no conflict with the GMP or ISO 13485. Because the

on-site audit is to be conducted selectively, for initial application for

registration of imported medical devices, the NMPA will accept the QMS

qualification of the foreign applicants issued by the country of origin.

Concerning applicants from the EU (including UK), an ISO 13485 certificate

will be accepted as the manufacturer’s qualification by the NMPA. However,

special attention should be paid to the China specific requirements that

should be covered by the QMS for medical devices being or to be marketed

in China. For example, the PTR and applicable Chinese standards should be

included in the technical documentation according to Article 24 of the “Good

Manufacture Practice for Medical Devices”. And to study the overseas on-site

audit reports published by the CFDA is highly recommended. Among these

29 reports, the author of this master thesis found that aside from common

QMS non-conformities, other common non-conformities specific to Chinese

regulations have been found, including the items listed in Table 15 below.

Non-conformity items

Reports in

total

Chinese regulations not being (correctly) identified

[40] [41] [42] [43] [44]

[45] [46] [47] [49] [50] [52] [53]

Inconsistencies with the PTR / product standard

[39] [41] [43] [46] [51] [52]

[54]

Specifications / components being marketed in China without

CFDA approval

[39] [49]

(3)

ISO 13485:2016, Medical devices -- Quality management systems -- Requirements for

regulatory purposes

(4)

YY/T 0287-2017, Medical devices — Quality management systems — Requirements for

regulatory purposes (ISO 13845:2016, IDT*)

*IDT = identical

4. Discussion

Chinese IFU and label not meeting CFDA requirements

[42]

Clean room condition inconsistent with Chinese GMP

[48]

Notes:

a) 7 reports on the manufacturers based in the EU (including the UK);

b) 6 reports on the manufacturers based in the EU (including the UK);

c) Both reports on the manufacturers based in the UK.

Table 15: Non-conformities to Chinese regulations

Considering that the ISO 13485 certificate from the manufacturer based in

the EU (including the UK) is the mandatory qualification file to be submitted

for applications of imported medical devices, the non-conformities listed in

Table 15 are good examples that the compliance with ISO 13485 will not be

enough for the Chinese “Good Manufacture Practice for Medical Devices”

and other related Chinese regulations. The European manufacturers have to

identify applicable Chinese regulations as early as possible to ensure the

regulatory compliance of their medical devices to be and being marketed in

China.

It is worth noting that Chinese local medical device manufacturers have to

pass the on-site QMS audit before submitting the applications for their

products, while most of the medical devices manufacturers overseas have

never been audited on site by the CFDA. The non-execution of on-site QMS

audits to overseas medical device manufacturers is largely due to the

restrictions from practical and political aspects, such as manpower and visa

application. So far, China has no plan to join the “Mutual Recognition

Agreements” or accept audit reports issued by conformity assessment bodies

from other countries. Even though in reality the overseas on-site audits have

to be done selectively, the medical device manufacturers have the

responsibility to comply with Chinese regulations when marketing their

products in China. Hence, the urgency of identifying and adopting Chinese

regulations should not be measured by the “risk” of being selected for the

overseas on-site audit.

4.6 Special review procedure for innovative devices

For initial registration application of imported medical devices in China, the

approval from the country of origin has always been the basic requirement; it

4. Discussion

is the mandatory document to be submitted as requested by both the

previous (2004) version and current (2014) version of the “Provisions for

Medical Device Registration”, and by the current (2014) version of the

“Regulations for the Supervision and Administration of Medical Devices”. A

positive sign from the proposed “Regulations for the Supervision and

Administration of Medical Devices (draft version)” is the exemption on the

marketing approvals from the country of origin (= valid certificate of a Notified

Body for European applicants) for innovative medical devices. However,

there are many restrictions on the qualification as an “innovative” device.

Table 16 below shows the provisions concerning the requirements of

marketing approval from the country of origin in the current version (2014)

and proposed draft (2017) of the “Regulations for the Supervision and

Administration of Medical Devices” (note: translated into English by the

author of this master thesis).

"Regulations for the Supervision and Administration of Medical Devices"

Current version (2014)

Proposed version (2017)

Article 11:

…

For applications of imported class II and

class III medical devices, the marketing

approval from the country of origin for

the product to be marketed in China

should be submitted to the CFDA by the

agent.

…

Article 11:

…

For applications of imported class II and

class III medical devices, the marketing

approval from the country of origin for

the product to be marketed in China

should be submitted to the NMPA by the

agent. For innovative medical devices

that have not been marketed outside

China yet, the marketing approval from

the country of origin can be exempted.

…

Table 16: Requirement on marketing approval from the country of origin

As the proposal showed already, the exemption will only apply to devices that

have not been put on the market yet. Additionally, the NMPA also tightened

the eligibility criteria to narrow down the applicants. In 2018 the NMPA issued

the final version on the special review procedure of innovative medical

devices, further restricting the qualified innovative medical devices to medical

devices that have a Chinese patent and the qualification application should

4. Discussion

be submitted within 5 years after the publish date of its Chinese patent. The

qualification of the patent will be reviewed during the expert meetings.

Despite all the restrictions, the proposed exemption on the marketing

approval from the country of origin is still a positive sign that China is trying to

show more favour to innovative medical devices. And this is not the first

positive sign. In 2014 the CFDA has already issued a draft on the special

review procedure of innovative medical devices, enabling earlier interaction

with the reviewer and reducing queuing time during the testing and review

procedures for qualified innovative medical devices. Although such special

procedure will be good news to manufacturers of innovative medical devices

who want to market their products in China as soon as possible, the

procedure itself emphasizes that the technical requirements will not be

compromised and the necessary procedures will not be omitted, meaning

that if the foreign manufacturers wants to put their innovative medical device

onto the market of China soon, they should be prepared for the requests on

conducting thorough tests in China; and while the queuing time during the

testing and review procedures will be shortened, the actual procedures of the

testing and reviews could not be accelerated. In fact, whenever expert

meetings are involved, the technical review would most likely take longer

time and additional testing requests are to be expected. Even so, the chance

of early interaction with the reviewer and experts will be really helpful to

optimise the test design and avoid unnecessary cost and time during the

preparation and review phases.

5. Conclusion and outlook

Although compared to medical device regulations in the EU, the Chinese

medical device regulations are relatively immature and are being revised

more frequently, the trend indicates that China is attempting to simplify the

application procedures and be more open to new medical technologies while

strengthening on the post market surveillance.

For many years, in China, the marketing approval of a medical device would

be largely based on local testing data, including local type testing data and

local clinical trial data. Although it will take time to review the system to

accept respectively to implement alternative approaches, the up to now

respectively amended and new elaborated regulations have already shown

positive signs. Now being a regular member of the ICH as well as a full

member of the IMDRF, the NMPA actively tries to accelerate the procedure

to adopt harmonized standards and get in line with international regulations.

It is to be expected that the discrepancies between Chinese and EN ISO (=

European and International) standards and EU and FDA regulations will be

less significant in the future.

Regarding post market surveillance, now that the MDR also strengthens the

requirements for medical devices being marketed in the EU, to improve the

plan, implementation and documentation of the post market surveillance

activities will be the major tasks of European manufacturers. Hence the gap

between the requirements on post market surveillance in the EU and in

China should be less significant if the manufacturer complies with the MDR.

Although the signs are positive, the reform of the medical device regulation

system in China will definitely take time. And considering the economic and

political differences, China specific requirements will still exist. For European

medical device manufacturers that prepare to enter the market of China or

have already been marketing their products in China, it is recommendable to

keep up with the development of Chinese medical device regulations. The

early and correct input of Chinese regulations will be the best approach to

avoid unnecessary time, cost and effort in later stages. Identifying the correct

Chinese requirement in the design phase will be more cost-effective than

5. Conclusion and outlook

trying to cover the gap later during the application phase (for details refer to

chapter 4 of this master thesis).

Because the medical device regulations, guidelines and standards in China

will be issued in Chinese only, language could be an issue to European

manufacturers. However, it is not impossible for any foreign manufacturer to

keep up with the new Chinese regulations, as long as the responsibilities of

the agent have been clearly defined and the communication between the

agent and the foreign manufacturer is efficient enough.

Table 17 and Table 18 below list the latest version of some very important

Chinese regulations and helpful guidelines for medical devices.

Regulations

Issue date

Effective

date

Regulations for the Supervision and Administration of

Medical Devices (Decree No. 650 of the state council)

2014-03-07

2014-06-01

Provisions for Medical Device Registration (Decree No.

4 of the CFDA)*

2014-07-30

2014-10-01

Provisions for Instructions and Labels of Medical

Devices (Decree No. 6 of the CFDA)*

2014-07-30

2014-10-01

Good Manufacture Practice for Medical Devices

2014-12-29

2015-03-01

Good Clinical Practice for Medical Devices (Decree

No. 25 of the CFDA)

2016-03-01

2016-06-01

Provisions for Recalls of Medical Devices (Decree

No.29 of the CFDA)

2017-01-25

2017-05-01

Rules for Classification of Medical Devices (Decree

No.15 of the CFDA)*

2015-07-14

2016-01-01

Medical Device Classification Catalogue

2017-08-31

2018-08-01

Provisions for Adverse Events Surveillance and Re-

assessment of Medical Devices” (Decree No. 1 of the

SAMR)

2018-08-13

2019-01-01

* English version available. Links given in “References”.

Table 17: List of important Chinese regulations

Guidelines

Issue date

Guideline on drafting Product Technical Requirement

2014-05-10

Guideline on the Clinical Evaluation of Medical Devices

2015-04-01

Guideline on Division of Registration Unit

2017-11-17

5. Conclusion and outlook

Guideline on Accepting Foreign Clinical Data

2018-01-10

Guideline on Initial Registration of Imported Medical Devices

2018-09-30

Guideline on Change Application of Imported Medical Devices

2018-09-30

Guideline on Renewal Application of Imported Medical Devices

2018-09-30

Table 18: List of useful Chinese guidelines

6. Summary

While being an attractive market to foreign medical device manufacturers,

China is also considered to be one of the difficult markets due to the Chinese

specific and rapidly changing regulations. Especially since the former State

Food and Drug Administration (SFDA) reconstructed into the China Food and

Drug Administration (CFDA) in 2013, the medical device regulations in China

went through many changes, including major ones. In 2014, two fundamental

regulations, the "Regulations for the Supervision and Administration of

Medical Devices"

and the "Provisions for Medical Device Registration" have

been revised and came into force. Subsequently other regulations have been

revised and new regulations and guidelines have been issued as well,

providing clarifications to critical issues such as the requirement on clinical

evaluations. The CFDA attempted to better normalize the review and

approval procedures for medical device applications.

In March 2018 the CFDA has been reconstructed into the National Medical

Products Administration (NMPA), which is now under the supervision of the

State Administration for Market Regulation (SAMR). The post market

surveillance of medical devices in China will be strengthened. New changes

to the medical devices regulations in China are to be expected.

This master thesis took a general but systematic review of the current

medical device regulations in China that have come into force since 2014,

analysing the gap between the regulatory requirements in China and in the

EU, with the focus on application procedures. This thesis also identified some

of the most intriguing new trend in the recent changes of Chinese medical

device regulations and discussed the possible challenges and opportunities

to be faced by European medical device manufacturers that comply already

with the medical device regulations in the EU. According to the author’s

opinion, even though China will remain challenging to foreign manufacturers

for quite some time, the recent changes of Chinese medical device

regulations indicated positive signs of better normalized procedures.

Although language could be an issue, as long as the foreign manufacturers

manage the communication with their local agents effectively, it’s not

impossible to keep up with the regulation changes in China. Besides,

identifying the local specific requirements as early as possible will definitely

6. Summary

be more helpful than trying to cover the gap later, which applies to any other

markets as well.

Acknowledgement

I'm extremely grateful to my supervisor Dr. Ehrhard Anhalt for his time and

patience, and for his insightful comments during the review of this master thesis.

I'm also grateful to Dr. Santiago Figueroa-Perez for taking the time to review this

master thesis.

Additionally, I would like to thank Ms. Barbara Röcher, Ms. Jasmin Fahnenstich,

Ms. Eva-Maria Eibl and Ms. Charlotte Klement for their helpful support and

excellent organization during the courses.

References

VII

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LLC, http://samr.cfda.gov.cn/WS01/CL2026/225516.html. Accessed on 7 January 2019.

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(only Chinese version available)

[45] CFDA. (2018). Notification on the overseas on-site audit report - STAR Medical Co., Ltd,

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Australia Pty, Ltd., http://samr.cfda.gov.cn/WS01/CL2026/225518.html. Accessed on 7

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[47] CFDA. (2018). Notification on the overseas on-site audit report - 3M Health Care,

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Co.Medizintechnik KG, http://samr.cfda.gov.cn/WS01/CL2026/222855.html. Accessed

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[50] CFDA. (2017). Notification on the overseas on-site audit report - BIOKIT, S.A.,

http://samr.cfda.gov.cn/WS01/CL2026/217544.html. Accessed on 7 January 2019. (only

Chinese version available)

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URGO, http://samr.cfda.gov.cn/WS01/CL2026/217544.html. Accessed on 7 January

2019. (only Chinese version available)

[52] NMPA. (2018). Notification on the overseas on-site audit report - Rayner Intraocular

Lenses Limited, http://www.nmpa.gov.cn/WS04/CL2195/334552.html. Accessed on 18

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[53] NMPA. (2018). Notification on the overseas on-site audit report - OPHTEC B.V.,

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Erklärung

Hiermit erkläre ich an Eides statt, die Arbeit selbständig verfasst und keine

anderen als die angegebenen Hilfsmittel verwendet zu haben.

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