Clinical Evaluation Of Continuous Glucose Monitoring Systems

Clinical Evaluation A/0

Clinical Evaluation

Of

Continuous Glucose Monitoring Systems


Table of Content

Table of Content 2

1 Summary 3

2 Scope of the clinical evaluation 3

2.1 Product description 3

2.2 Intended use 3

2.3 Contraindication and Caution 5

2.3 Type/models 5

2.4 Product specification 5

2.5 Labelling 12

3 Clinical background, current knowledge, state of the art 12

4 Device under evaluation 14

4.1 Type of evaluation 14

4.2 Demonstration of equivalence 14

4.3 Clinical data held and generated by the manufacturer 19

4.4 Clinical data from literature 25

4.5. Summary and appraisal of clinical data 29

4.6. Analysis of the clinical data 37

5. Conclusions 41

6. Date of the next clinical evaluation 42

7. Dates and signatures 42

8. Qualification of the responsible evaluators 43

References 44

Appendix 1: Main Study Findings and Authors’ Conclusions 46


1 Summary

This clinical discussion is developed to provide a comprehensive analysis of available

pre and post market clinical data relevant to the intended use of Continuous Glucose

Monitoring Systems, to ensure that there is sufficient evidence to confirm compliance

with relevant essential requirements for safety and performance when using the device

according to the manufacturer’s instructions for use.

2 Scope of the clinical evaluation

2.1 Product description

The Continuous Glucose Monitoring Systems is consist of a disposable sensor,

transmitter, App，and analysis software, in which the core device is the sensor electrode.

It is recommended to wear the sensor to the abdomen and minimize activities extent.

The sensor electrode chemically reacts with glucose in the hypodermic tissue fluid to

generate an electrical signal. Transmitter analysis and calculates the electrical signal,

and generates the blood glucose values, which is transmitted to the mobile App. The

user analysis software downloads and collects data from the mobile App for processing

and analysis, then gives reports.

During the monitoring period, at least two finger blood glucose values need to be

inputted into the Continuous Glucose Monitoring Systems every day for calibration. The

Continuous Glucose Monitoring Systems calculates an average of every three minutes.

The Continuous Glucose Monitoring Systems can record 480 glucose readings every 24

hours, continuously monitor the blood glucose data for 14 days and form a continuous

blood glucose curve. In addition, dining, sports, medication and other activities can be

recorded.

Critical components and materials of the product are listed as follows.

Raw material list of Sensor

Type Level Material


Sensor

electrode

A 铂铱丝 Platinum iridium wire

聚氨酯 Polyurethane (PU)

parylene 绝缘层 Parylene insulation

导电银浆 conductive silver paste

葡萄糖氧化酶 Glucose oxidase

氨丙基封端聚乙二醇 Polyethylene Glycol

Applicator A 无防胶布 Non-woven tape

穿刺针 puncture needle

顶针 thimble

导向针 Guide pin

塑胶件 plastic

导电橡胶 Conductive rubber

压簧 Press spring

焊脚电池 Soldering battery

无菌包装袋 Aseptic packaging bag

Raw material list of transmitter

Model Type Authentication information/material

T POINT POWER Conductive

needle Brass

T POINT S Conductive

needle Brass

PCB Printed circuit

board PCBA-X2

Shell Epoxy res

2.2 Intended use

The device is intended for continuous or periodic recording of interstitial fluid glucose


levels in adult patients with diabetes aged 18 or older. The system is designed for

patients to use at home and in medical institutions. The information is intended to supple,

rather than replace, the information obtained from standard glucose monitor like

traditional glucose meter and is intended to detect trends and track patterns and to

provide reference information for patients to manage diabetes. The system provides

real-time blood glucose value, which is received and read by the App. The blood glucose

value data can be further imported into the software for analysis of historical blood

glucose values.

2.3 Contraindication and Caution

Part of sensor electrode need to pierce the skin, so it is recommended that allergy and

skin ulcers people use the device cautiously. The product must be removed before

magnetic resonance imaging (MRI).

Taking acetaminophen while wearing the sensor may falsely raise your sensor glucose

readings.

2.4 Type/models

i3

2.5 Product specification

The Continuous Glucose Monitoring Systems is consist of a disposable sensor,

transmitter, App，and analysis software, in which the core device is the sensor electrode.


Sensor

Transmitter

APP

Analysis software

Figure 1 Continuous Glucose Monitoring Systems

2.5.1 Sensor overview

Safety lock

Button

Sensor base and Adhesive patch

Figure 2 Sensor

The continuous glucose monitoring sensor is a product with a sterile sealed pouch. The

sensor is mainly composed of an applicator, a base and a sensor electrode. The base

consists of a PC base and an adhesive patch. The sensor electrode is divided into three


layers: semi-permeable membrane, glucose oxidase layer and microelectrode. Insert

the sensor electrode into the subcutaneous tissue of the abdomen and remove the

applicator. The base is attached to the abdomen for up to 14 days of monitoring. Please

discard disposable sensor after wearing.5.6.1.1 The performance parameters of sensor

Table 1 The performance parameters of sensor

Model No. SI3-WL-03

Measurement range 2.2-22.2 mmol/L

Effective working

time 14 days

Calibration method Glucose meter

Calibration range 2.2-22.2 mmol/L

Storage conditions Temperature：2oC-25 oC；

Relative humidity：15%-85%

Transport conditions Normal temperature transportation

Rated voltage d.c. 3V

Battery lifetime No less than 14 days

Sterilization method Irradiation sterilization

Validity period 8 months

2.5.2 Transmitter overview

The continuous glucose monitoring transmitter is a component fixed on the sensor base

with chips. Once the transmitter is fixed in the sensor base and the sensor probe is

activated through the App, the transmitter sends the blood glucose message to the App.

When properly worn, the transmitter and App have a transmission range of 2 m without

obstruction. Wireless connection in the water is not very good, so the range of

connections in places like swimming pools, bathtubs and waterbeds will be even

smaller.

2.5.2.1 The performance parameters of transmitter

Table 2 The performance parameters of transmitter


Model No. TI3-WL -03

Size length33 mm *width19 mm *height 4 mm

Weight of transmitter 3.7 g

Display interval 3 min

Calibration method Glucose meter

Calibration frequency 2 times / day（24h）

Data receiving range 2 m（Obstruction free）

Historical data storage

capacity No less than 14 days

Operation mode Continuous working

Power support Internal power supply

Classification Type BF

Protection grade IP27

Working conditions

（After the transmitter placed

in the sensor base）

Temperature：10 oC-40 oC；


Atmospheric pressure 70kPa-106 kPa

Storage conditions Temperature：0 oC-45 oC；


Validity period 36 months

Transport protocol Bluetooth 4.0

Operating Frequency Range 2400~2483.5MHz

Maximum Output Power 6dBm

25.5.2.2 EMC Statement

Guidance and manufacture's declaration – electromagnetic emissions

The Continuous Glucose Monitoring Systems is suitable for use in the specified

electromagnetic environment (s) and it has met the following standard’s emission

requirements.

Phenomenon Home healthcare environment

Conducted and radiated RF emissions CISPR 11, Group 1, Class B

Harmonic distortion N/A


Voltage fluctuations and flicker N/A

Guidance and manufacture's declaration – electromagnetic immunity

The Continuous Glucose Monitoring Systems is suitable for use in the specified

electromagnetic environment (s) and it has met the following immunity test levels.

Higher immunity levels may cause the Continuous Glucose Monitoring Systems’s

essential performance lost or degraded.

Phenomenon Basic EMC standard or

test method

Home healthcare facility environment

Electrostatic

discharge IEC 61000-4-2

+/- 8 kV contact

+/- 2 kV, +/- 4 kV, +/- 8 kV, +/- 15 kV air

Radiated RF EM

fields IEC 61000-4-3

10V/m

80MHz-2.7GHz

80%AM at 1kHz

Proximity fields from

RF

wireless

communications

equipment

IEC 61000-4-3

See the RF wireless communication

equipment table in "Recommended

minimum separation distances".

Rated power

frequency magnetic

fields

IEC 61000-4-8 30A/m; 50 Hz or 60Hz

Electric fast

transients bursts IEC 61000-4-4 N/A


Surges IEC 61000-4-5 N/A

Conducted

disturbances

induced by RF fields

IEC 61000-4-6 N/A

Voltage dips IEC 61000-4-11

N/A

N/A

Voltage

interruptions IEC 61000-4-11 N/A

Recommended minimum separation distances

Nowadays, many RF wireless equipment have being used in various healthcare

locations where medical equipment and/or systems are used. When they are used in

close proximity to medical equipment and/or systems, the medical equipment and/or

systems’ basic safety and essential performance may be affected. Continuous

Glucose Monitoring Systems has been tested with the immunity test level in the below

table and meet the related requirements of IEC 60601-1-2:2014. The customer and/or

user should help keep a minimum distance between RF wireless communications

equipment and Continuous Glucose Monitoring Systems as recommended below.

Test

frequency

(MHz)

Band

(MHz) Service Modulation

Maximum

power

(W)

Distance

(m)

Immunity

test level

(V/m)

385 380-390 TETRA 400

Pulse

modulation

18Hz

1.8 0.3 27

450 430-470 GMRS 460

FRS 460

FM

± 5 kHz

deviation

1 kHz sine

2 0.3 28

710 704-787

LTE Band

13, 17

Pulse

modulation 0.2 0.3 9

745


780 217Hz

810

800-960

GSM

800/900,

TETRA 800,

iDEN 820,

CDMA 850,

LTE Band 5

Pulse

modulation

18Hz

2 0.3 28

870

930

1720

1700-1990

GSM 1800;

CDMA

1900;

GSM 1900;

DECT;

LTE Band 1,

3,

4, 25; UMTS

Pulse

modulation

217Hz

2 0.3 28

1845

1970

2450 2400-2570

Bluetooth,

WLAN,

802.11

b/g/n,

RFID 2450,

LTE Band 7

Pulse

modulation

217Hz

2 0.3 28

5240

5100-5800

WLAN

802.11

a/n

Pulse

modulation

217Hz

0.2 0.3 9 5500

5785

Table 3 EMC Statement

2.5.3 APP overview

Continuous glucose monitoring App is a mobile medical application for Continuous

Glucose Monitoring Systems to receive and process glucose readings. The software

displays blood glucose readings, trend curves, trend arrows, and transmitter status. It

has functions of adding events, event records, wearing records, alarm notifications,

reading lists, statistical analysis, data export, account management and so on.


Figure 3 Main interface of App

The main interface of App mainly displays blood glucose readings, trend curves and

trend arrows. App and transmitter can be connected through bluetooth, pairing for data

communication. A blood glucose meter is also needed to be used with the Continuous

Glucose Monitoring Systems.

2.5.4 Analysis software overview

Continuous glucose monitoring analysis software is the auxiliary software of Continuous

Glucose Monitoring Systems. It can process the data collected in the App and generate

analysis reports.

2.6 Labelling

Label and IFU have been established, e.g. label sample is given in file no.

I3/WJ-XT-BQ-01, and IFU is given in file no. I3/WJ-XT-SMS-01.

3 Clinical background, current knowledge, state of the art

The blood sugar of a person with diabetes is continuously changing every minute of the

day throughout the person’s life. Patients may use glucometers to check blood sugar,

but this gives the value of blood sugar only at the particular time when the test is done.


However, since blood sugar levels of a patient are changing from minute to minute,

checking simply with blood glucose meters may not be sufficient. Additionally, 60% of

glucose lows may not be revealed with self-monitoring of blood glucose (SMBG) alone.

Another standard way to monitor blood glucose is through the measurement of

glycosylated hemoglobin, more commonly known as hemoglobin A1c (HbA1c). But

again, HbA1c does not tell the whole story as while it provides information about glucose

exposure it is not able to track glycemic variability. HbA1c is a very useful test to detect

how well blood sugar is controlled over the previous 3 months. However, since HbA1c

indicates the average blood sugar, it does not give a correct picture of how much

fluctuations occur. In fact, if a patient has frequent low blood sugar, it could result in low

HbA1c (because HbA1c denotes an average value) and a false sense of security to the

patient and doctor, even when the blood sugar is often high and is actually poorly

controlled.

Thus, while SMBG and HbA1c are important—they do not tell us the complete

picture—especially information on glycemic variability of the patient.

Continuous glucose monitoring (CGM) can help complete the picture for a patient’s

glucose control. An effective way to monitor sugar levels to understand how the blood

sugar is changing throughout the day and to understand the state of glycemic

excursions in a patient is with the help of a technology called Continuous Glucose

Monitoring Systems (CGMS). It keeps a record every 3 minutes so that we can get 480

readings per day during the CGMS study period. A tiny, sterile, flexible electrode is

inserted just under the skin that measures glucose in the interstitial fluid (ISF). This data

is then uploaded onto a computer and clearly visible in the form of a graph which any

one can understand.

There are plenty of patients who have high blood sugar at odd times of the day which is

not detected by the routine tests like fasting blood sugar (FBS) and postprandial blood

sugar (PPBS) (blood sugar after food) or who are unaware that they may be

experiencing low blood sugars at night. The use of a CGMS can provide essential

information to the doctor to allow him/her to appropriately modify the treatment of their

patients to get better control of blood sugar throughout the day.


Continuous glucose monitoring shows the complete picture of glucose activity, not just

snapshots of glucose levels. It allows users and clinicians to gain more insight by

providing real-time information about glucose levels and showing glucose trends

between finger sticks, leading to improved glucose control. CGM also provides

additional information beyond the “average” of overall glucose levels that is represented

by HbA1c. A recent study has shown that patients who use CGM at least 6 days a week

substantially lower their A1c levels without an increase in hypoglycemia, compared with

patients who use it less frequently. Continuous glucose readings allow patients to better

manage their diabetes by intervening on a real-time basis to reduce the frequency and

severity of hypoglycemic or hyperglycemic episodes. Patients can learn how diet,

exercise, medication, lifestyle and episodes of illness affect their glucose levels.

Furthermore, historical analysis provides insights for both patients and health care

professionals (HCPs) that can be translated into treatment adjustments and optimization.

Several studies have demonstrated a significant difference in A1c outcomes on the

basis of adjustments in insulin regimens in response to CGM.3-5 Hirsch (2002) has also

demonstrated that use of CGM in clinical practice would provide the required monitoring

tool to minimize glycemic variability and superoxide overproduction and may potentially

reduce diabetic complications.

4 Device under evaluation

4.1 Type of evaluation

Assessment of safety and performance of the devices in scope is based on several data

sources, including compliance with recognized standards, biocompatibility assessment

of the devices, and verification activities as well as clinical from relevant published

clinical literatures. The following is a presentation of these various data sources and the

evaluation thereof.

4.2 Demonstration of equivalence

The Continuous Glucose Monitoring Systems is as safe and effective as the predicate


device as presented in Table 1.

Continuous Glucose Monitoring Systems is equivalent to the devices based on the

comparison given in Table 1.

Table 1 Equivalence demonstration

Characteristics

Continuous Glucose Monitoring

Systems

(Model: i3)


Systems

(Model: Dexcom G6)

Comparison

Product

Appearance

Sensor

Transmitter

APP

Analysis software

Substantially

equivalent.

Intended Use

The device is intended for

continuous or periodic recording

of interstitial fluid glucose levels

in adult patients with diabetes

aged 18 or older. The system is

designed for patients to use at

home and in medical institutions.

The device is intended to detect

trends and track patterns and to

provide reference information for

patients to manage diabetes.

The Dexcom G6 Continuous

Glucose Monitoring Systems

(Dexcom G6 System) is a real

time, continuous glucose

monitoring device indicated for the

management of diabetes in

persons age 2 years and older.

The Dexcom G6 System is

intended to replace fingerstick

blood glucose testing for diabetes

treatment decisions. Interpretation

of the Dexcom G6 System results

should be based on the glucose

Substantially

equivalent.

Intended use

and applicable

population of

Dexcom G6 is

wider than i3.


trends and several sequential

readings over time. The Dexcom

G6 System also aids in the

detection of episodes of

hyperglycemia and hypoglycemia,

facilitating both acute and

long-term therapy adjustments.

The Dexcom G6 System is also

intended to autonomously

communicate with digitally

connected devices, including

automated insulin dosing (AID)

systems. The Dexcom G6 System

can be used alone or in

conjunction with these digitally

connected medical devices for the

purpose of managing diabetes.

Sensor specification

Sensor

Appearance

Safety lock

Button

Sensor base and Adhesive patch

Substantially

equivalent.

Glucose Range 2.2-22.2 mmol/L 40-400 mg/dL (2.2-22.2 mmol/L) Same

Sensor Life 14 days Up to 7 days Substantially

equivalent.

Calibration Glucose meter Commercially available blood Same


glucose meter

Calibration

Range 2.2-22.2 mmol/L 40-400 mg/dL Same

Storage

Condition

Temperature：2oC-25 oC；


Temperature: 36° F-77° F

Humidity: 15%-85% RH

Same

Sterilization Sterile by irradiation Sterile by radiation Same

Transmitter Specification

Dimensions

(Including Sensor

Pod)

length32 mm

width15.5 mm

height7.8 mm

Length: 1.5 inches

Width: 0.9 inches

Thickness: 0.5 inches

Minor

difference

does not

change

indication for

use.

Weight (Including

Sensor Pod) 6.2 g 0.4 ounces

Minor

difference

does not

change

indication for

use.

Power Supply

Internal power supply（battery in

base of sensor）

Silver oxide batteries (not

replaceable)

Minor

difference

does not

change

indication for

use.

Operational Temperature：10°C-40°C； Ambient temperature is 10° C-42° Substantially


Conditions Relative humidity：10%-95% C (50° F-107.6° F)

Equilibrium temperature of less

than 0.5° C (0.9° F) above

ambient


equivalent.

Storage

Conditions

Temperature：0°C-45°C；


Temperature: 32° F-113° F


Substantially

equivalent.

Atmospheric

pressure 70kPa-106 kPa

-1300 feet to 13800 feet

(Operating Altitude)

Substantially

equivalent.

Limited Warranty 112 days 3 months

Does not

change

indication for

use

Moisture

Protection IP27

IP28: Protection against insertion

of large objects and immersion in

water

for up to 8 feet for 24 hours

Minor

difference

does not

change

indication for

use.

Protection

Against Type BF

Electrical Shock Type BF applied

part Same

Data

Communication

Range

2m 20 feet

Minor

difference

does not

change

indication for

use.


Data of the Predicate device (Dexcom G6) was extracted from Dexcom G6 IFU.

These two Continuous Glucose Monitoring Systems are both composed of a disposable

sensor, transmitter，analysis software and are designed for patients to use at home and

in medical institutions. The Dexcom G6 Continuous Glucose Monitoring Systems can

replace finger blood glucose monitoring and used in children more than 2 years old.

Dexcom G6 has wider intended use and applicable population, it contains the

functionality of i3. Thus, the safety and effectiveness of i3 can be proved.

CE certificate Number for the compared device: CE 591560

4.3 Clinical data held and generated by the manufacturer

4.3.1 Applicable standards

Assessment of safety and performance of the Continuous Glucose Monitoring Systems

is in part based on conformance with recognized standards which have established that

the device has been designed and manufactured with appropriate controls, the materials

of the subject device are appropriate for the intended use and the product is

appropriately packaged. The devices are in substantial conformance with the

recognized standards outlined in Table 2 below. Compliance with these standards

provides evidence for the safety and performance.

Table 2 Compliance Standards for Continuous Glucose Monitoring Systems

No. Standards Reference Content

1 EN ISO 15223-1 2016

Medical devices. Symbols to be used with medical

device labels, labelling and information to be

supplied. Part 1: General requirements

2 EN1041 2008/A1:20

13

Information supplied by the manufacturer with

medical devices

3 EN ISO 13485 2016/AC:20

16

Medical devices-quality management

systems-requirements for regulatory purposes

4 EN ISO 14971 2012 Medical devices-application of risk management to

medical devices


5 EN 60601-1 2012+A1+A

2

Medical electrical equipment-part1: general

requirements for basic safety and essential

performance

6 EN60601-1-2 2015

Medical electrical equipment-part1-2: general


performance-collateral standard:

electromagnetic compatibility-requirements and

tests

7 EN60601-1-6 2010

Medical electrical equipment-part1-6: general


performance-collateral standard: usability

8 EN 60601-1-11 2010

Medical electrical equipment — Part 1-11: General


performance — Collateral standard: Requirements

for medical electrical equipment and medical

electrical systems used in the home healthcare

environment

IEC 60601-1-11:2010

9 EN ISO 10993-1 2009/AC:20

10

Biological evaluation of medical devices - Part 1:

Evaluation and testing within a risk management

process

10 EN ISO 10993-3 2014

Biological evaluation of medical devices — Part 3:

Tests for genotoxicity, carcinogenicity and repro-

ductive toxicity (ISO 10993-3:2014)

11 EN ISO 10993-5 2009 Biological evaluation of medical devices — Part 5:

Tests for in vitro cytotoxicity (ISO 10993- 5:2009)

12 EN ISO 10993-6 2009


Tests for local effects after implantation (ISO

10993-6:2007)

13 EN ISO

10993-10 2013

Biological evaluation of medical devices – Part 10:

Tests for irritation and skin sensitization (ISO

10993-10:2010)

14 EN ISO

10993-11 2009


Tests for systemic toxicity (ISO 10993- 11:2006)

15 EN ISO

10993-12 2012


Sample preparation and reference materials (ISO

10993-12:2012)

16 EN ISO 14644-1 2015

Cleanrooms and associated controlled

environments - Part 1: Classification of air

cleanliness

17 EN ISO 14644-2 2015


environments - Part 2: Specifications for testing and

monitoring to prove continued compliance with ISO


14644-1

18 ISO 14698-1 2003


environments - Biocontamination control - Part 1:

General principles and methods

19 ISO 14698-2 2003


environments - Biocontamination control - Part 2:

Evaluation and interpretation of biocontamination

data

20 EN 556-1 2001+AC:2

006

Sterilization of medical devices - Requirements for

medical devices to be designated "STERILE" - Part

1: Requirements for terminally sterilized medical

devices

21 EN ISO 11137-1 2015

Sterilization of health care products - Radiation -

Part 1: Requirements for development, validation

and routine control of a sterilization process for

medical devices

22 EN ISO 11137-2 2015 Sterilization of health care products - Radiation -

Part 2: Establishing the sterilization dose

23 EN ISO 11607-1 2009

Packaging for terminally sterilized medical devices -

Part 1: Requirements for materials, sterile barrier

systems and packaging

24 EN ISO 11607-2 2006

Packaging for terminally sterilized medical devices -

Part 2: Validation requirements for forming, sealing

and assembly processes

25 EN ISO 11737-1 2006+AC:2

009

Sterilization of medical devices - Microbiological

methods - Part 1: Determination of a population of

microorganisms on products

26 EN ISO 11737-2 2009

Sterilization of medical devices - Microbiological

methods - Part 2: Tests of sterility performed in the

definition, validation and maintenance of a

sterilization process

27 IEC 60529 2013 Degrees of protection provided by enclosures

28 ISTA 2A 2011 Packaged-Products 150lb (68kg) or less

29 WEEE (2002/96/E

C)

Waste Electrical and Electronic Equipment (WEEE)

Directive

30 RoHS (2011/65/E

U) Restriction of Hazardous Substances

31 EN62304 2006+

A1:2015

Medical device software. Software life-cycle

processes

32 EN62366-1 2015 Medical devices-application of usability engineering

to medical devices


33 93/42/EEC 2007 Council directive 93/42/EEC of 14 June 1993

concerning medical devices

34 MEDDEV 2.7.1

Rev 4 2016

Clinical evaluation: a guide for manufacturers and

notified bodies.

Directives 93/42/EEC and 90/385/EEC.

35 IEC 62133 2012

Secondary cells and batteries containing alkaline or

other non-acid electrolytes – Safety requirements

for portable sealed secondary cells, and for

batteries made from them, for use in portable

applications

36 RED 2014/53/EU Radio Equipment Directive

4.3.2 Test report

See attached

4.3.2.1 Safety of Medical electrical Equipment 产品安全报告

Safety of medical electrical equipment testing of the device was performed in

accordance with technical standards applied. Refer to the following protocols

and reports.

Document Title 标准号 Document Number 测试报告号

EN 60601-1 Report no. 50276561 001

EN 60601-11

4.3.2.2 Electromagnetic Compatibility 电磁兼容

Electrical compatibility testing of the device was performed in accordance with

the technical standards applied. Refer to the following protocols and reports.


EN 60601-1-2 Report no. 50273828 001

4.3.2.3 Biological Safety 生物相容性评估报告

Biological Safety testing of the device was performed in accordance with the

technical standards applied. Refer to the following protocols and reports.


EN ISO 10993-1 Report no. I3/BG-XT-002

4.3.2.4 Usability 可用性报告

The device was evaluated against the standards applied. Refer to the

following reports for the scenarios tested.


EN62366

EN 60601-1-6

Report no. I3/BG-XT-001


4.3.2.5 Sterilization Validation 灭菌验证报告

The Sensor is supplied steriled, and sterilized by Radiation sterilization to

ensure SAL≥10 -6. The Radiation sterilization is not conducted in-house but

outsourced to the subcontractor: Suzhou CNNC Huadong Radiation Co., Lt 苏

州中核华东辐照有限公司

The subcontractor has established a QM system according to EN ISO 13485

for provision of Radiation sterilization service of medical device according to

EN ISO 11137. The subcontractor has got EN ISO 13485 certificate and under

annual surveillance audit by the Certification Body. The QMS certificate and

subcontract agreement are enclosed as attachment to this file:

<灭菌协议文件编号>: Radiation Sterilization Subcontract Agreement

<灭菌公司的体系证书编号>: EN ISO 13485 certificate of the subcontractor

The sterilization process has been validated according to EN ISO 11137,

which has thereby determined the routine control and monitoring parameters.

Please refer to attachment:

Radiation sterilization validation report: CHF-TC/ML-19-07-WJ12

Sterilization Dose Setting report: CHF-TC/ML-19-06-SD06

For routine release of sterilization, the sterilization certificate will be provided

for each sterilization batch, reviewed and approved by Quality Department.

4.3.2.6 Sterile packaging system 无菌包装确认

The Sensors in the product are packaged in sterile barrier packaging system

which aims to ensure the sterile condition of the products inside the packaging

within specified shelf life. The primary package material is Tyvek1037b sealed

by heat-sealing machine.

The primary packaging process is evaluated and validated according to EN

ISO 11607-1/2. Please refer to attachment:

Packaging Validation Report 包装确认报告: CHF/TC-PH-19-07-25

Shelf-life validation 货架寿命验证报告: I3/BG-CG-005，I3/BG-FS-004

4.3.2.7 Transportation evaluation 包装运输试验


(ISTA)2A Report no. FTS1907074-2E-1/A,

FTS1907074-1E-1/A

4.3.2.8 Software evaluation report 软件评估报告


EN62304 Report no. I3/BG-RJ-001

Report no. I2/BG-RJ-W002

4.3.2.9 RED test report



2014/53/EU Report no. 50177806

4.3.2.10 ROHS test report Document Number 测试报告号

Document Title 标准号 Report no. 0154350467a001

2011/65/EU

Due to these test reports, the product has met the requirements of international

standards, and was proved to be safe and effective.

4.3.3 Marketing authorization

The manufacturer has established and applies a quality management system for

manufacturing and distribution of Continuous Glucose Monitoring Systems, and has

been certified according to Directive 93/42/EEC Annex V and EN ISO 13485 by the

following Notified Body:

Name: TÜV Rheinland LGA Products GmbH

Address: Tillystraße 2, 90431, Nürnberg, Germany

CE identifier: 0197

The conformity assessment by the Notified Body follows the procedure relating to the

EC declaration of conformity set out in Annex VII of MDD, coupled with the procedure

set out in Annex V of MDD.

The copy of the certificates is given in the following attachments:

• MDD Annex V Certificate #DD 60135736 0001, issued on 2019-06-05, valid until

2024-02-29;

• EN ISO 13485 certificate #SX 60135737 0001, issued on 2019-06-05, valid

until.2022-02-28.

4.3.4 PMS

The manufacturer instituted and kept up to date a systematic procedure to review

experience gained from devices in the postproduction phase and to implement

appropriate means to apply any necessary corrective action.

The requirements of the PMS should be in direct proportion to the risk associated with


the device.

In addition, the available scientific knowledge (e.g. long-term effects), market experience

with similar products, and manufacturer experience with the product or technology

should be considered.

No adverse incident or vigilance incident reported up to now.

4.4 Clinical data from literature

4.4.1 The object of literature review

A recent comprehensive literature search was performed to provide evidence of safety

and performance of the devices in question and to identify potential risks and hazards

pertinent to these devices in order to identify critical performance characteristics that

should be considered in the design and conditions for safe use relevant to the devices.

The specific objective and questions addressed by this current report include:

1. Does the literature present performance data pertinent to the equivalent

marketed device when used for the currently approved indications?

2. Does the literature present adverse/side-effect information pertinent to the

equivalent marketed device when used for the currently approved indications?

3. Are there previously unidentified reports/information relative to complications and

concerns associated with the application of subject devices?

4. Does the medical literature support a favorable risk/benefit analysis with respect

to the use of the subject devices for the stated indications?

4.4.2 Literature search and data source used

Information, addressing the performance and potential risk, associated with the use of

the device is retrieved from PUBMED, Cochrane Library, Clinical Trials and Science

Direct which operate independently from the manufacturer of the device(s).

This report is based mainly on original papers. Among the review articles, the data

sources used to obtain the references are listed as follows:


Elsevier Science Direct: http://www.sciencedirect.com/

Wiley Online Library: http://onlinelibrary.wiley.com/

Springer-Link: http://link.springer.com/

EBSCO: http://search.ebscohost.com/

Nature: http://www.nature.com/

Science: http://www.sciencemag.org/

Lancet: http://www.sciencedirect.com/science/journal/01406736

NEJM: http://www.nejm.org/

JAMA: http://jamanetwork.com/

BMJ: http://journals.bmj.com/

OVID: http://ovidsp.ovid.com/

Cochrane library: http://www.thecochranelibrary.com/view/0/index.html

A broad search of the literature was performed incorporating by both electronic and

manually search components and included publications from 2000 till 2018.

The electronic search was performed using PubMed and a focused Internet search (e.g.

Wanfang Med Online, Google Scholar) to retrieve any articles that may be relevant to

this Clinical Evaluation Report. The clinical literature search focused primarily on

English-language literature with search limits to restrict retrieved articles to human

clinical trials.

Within the database, “Related articles” were selected and reviewed to assure that all

articles of interest had been identified. Additionally, the citations of retrieved literature

were manually reviewed to determine if there were additional data/publications pertinent

to this CER.

The primary aim of this search was to identify literature describing clinical data and

experience with equivalent devices in either randomized or non-randomized clinical

evaluations.

http://www.thecochranelibrary.com/view/0/index.html


The following search terms applied in various combinations or alone were used during

the search:

⚫ Continuous Glucose Monitoring Systems

⚫ Dexcom G4/G5/G6

References were included if they provided data pertinent to the assessment of safety

and performance of the devices subject of this CER, or the subject matter was relevant

to the safety and complications relative to the use of the devices.

Studies were excluded if they did not satisfy the selection criteria mentioned above, if

they were published prior to 2008, duplicate publications of the same study.

One reviewer screened the titles and abstracts of the retrieved publications and

evaluated the full-text publications for the final article selection, according to selection

criteria mentioned above.

4.4.3 Literature review protocol

4.4.3.1 Literature review inclusion and exclusion criteria

Table 3: Literature review inclusion and exclusion criteria

Higher priority and included Lower priority or excluded

Studies which target the Continuous

Glucose Monitoring Systems in adult

of either gender.

Multicenter, prospective, randomized

controlled clinical trial.

Studies which use appropriate

qualitative and quantitative research

methods, including meta-analysis and

high-quality literature reviews.

Multiple-centered retrospective

Cadaveric studies

Animal studies

Case report

Biomechanical studies

Studies which focus on devices other than

the proposed or the equivalent device

Interventions that are not indicated for the

use of the proposed device

Expert views


studies

The data is generated from the

equivalent device.

Studies which contain insufficient

information to be able to undertake a

rational and objective assessment

Studies which has no appropriate statistical

analysis or limited power

4.4.3.2 Searching strategies and results

The following combination of search terms were used through the publications and the

subsequent searching result is shown in the table 4. Additional filters were selected as

Publishing Year to 2019/07/31.

Table 4: Search term and results

Search term Retrieved results Reference screened for

review


Systems Sort

by: Relevance Filters: Publication

date from 2000/01/01 to

2019/07/31

459 18

Dexcom G4/G5/G6 Sort

by: Relevance Filters: Publication

date from 2000/01/01 to

2019/07/31

85 8

By applying the up-mentioned inclusion and exclusion criteria, we synthesized the

articles retrieved from databases, a total of 17 articles were then selected for clinical

evaluation after eliminating duplication.


4.5. Summary and appraisal of clinical data

Qualifying clinical reports were rated in accordance with an evidence rating scale for

therapeutic studies as indicated in Table 5 and all were graded for suitability as

indicated in Table 6.

Table 5 Evidence Rating Scale for Therapeutic Studies

Level of

Evidence Qualifying Literature

I High-quality, multi-centered or single-centered, randomized controlled trial

with adequate power; or systematic review of these studies

II Less-quality, randomized controlled trial; prospective cohort study; or

systematic review of these studies

III Retrospective comparative study; case-control study; or systematic review of

these studies

IV Case series (no, or historical, control group)

V Expert opinion; case report or clinical example; or evidence based on

physiology, bench research or "first principles"

Table 6 Rating Scale for Suitability and Contribution

Suitability Criteria

Appropriate

device

Were the data generated from the device in

question?

D1 Actual device

D2 Equivalent device

D3 Other device

Appropriate

device application

Was the device used for the same intended use

(e.g., methods of deployment application, etc.)?

A1 Same use

A2 Minor deviation

A3 Major deviation


Appropriate

patient group

Where the data generated from a patient group that

is representative of the intended treatment

population e.g., age, sex, etc.) and clinical condition

(i.e., disease, including state and severity)?

P1 Applicable

P2 Limited

P3 Different population

Acceptable

report/data

collation

Do the reports or collations of data contain sufficient

information to be able to undertake a rational and

objective assessment?

R1 High quality

R2 Minor deficiencies

R3 Insufficient

information

Contribution Criteria

Data source type Was the design of the study appropriate? T1 Yes

T2 No

Outcomes

measured

Do the outcome measures reported reflect the

intended purpose of the device?

O1 Yes

O2 No

Follow up Is the duration of the follow-up long enough to

access whether duration of treatment effects and

identify complications?

F1 Yes

F2 No

Statistical

analysis

Has a statistical analysis of the data been provided

and is it appropriate?

S1 Yes

S2 No

Clinical

significance

Was the magnitude of the treatment effect observed

clinically significant?

C1 Yes

C2 No

Upon screening titles and abstracts from the searched literatures, potentially relevant

articles were retrieved for full-text review.

The characteristics of the clinical studies are summarized in Appendix 1. Appendix 1

presents the grading of recommendations and levels of evidence of the included

guidelines.

The Literature selected and scored is summarized in the table below (Table 5) and

classified as to the conclusions being either negative (-IPA) or positive (+IPA) with


respect to the use of the equivalent device. For some of the literature reports identified,

the outcomes were neither negative nor positive (denoted as “Balanced”).

Note that the average of the suitability and contribution scores awarded using the criteria

in Table 7 are shown independently but were also multiplied together to produce a

multiplier value for each dataset. The lower the multiplier value the greater the suitability

and contribution of the dataset to this clinical evaluation. For purposes of assigning a

suitability score, the studies performed in a human model is scored as P1 with respect to

appropriate patient group, and P2 if the study was performed in a non-human model,

parameters that were deemed not applicable (NA) or unable to determine (UTD) were

provided the highest score for the assessment. A limitation of this review is that there

were few randomized controlled trials available, with the majority of the publications

identified being prospective or case series (Level IV evidence).

Table 7 Outcome assessment for publications related to clinical data evaluation

Article Suitability

Score

Contribution

Score

Total

Score

Outcome/

Comment

Relevance to our

product

Efficacy and safety

comparison of

continuous glucose

monitoring and

selfmonitoring of blood

glucose in type 1

diabetes

5 5 25 +IPA

It is proved that CGM,

particularly its

real‑time system, has

a favorable effect on

glycemic control and

decreases the

incidence of

hypoglycemic

episodes in both adult

and pediatric patients

with type 1diabetes.

Beneficial effect of

real-time continuous

glucose monitoring

5 5 25 +IPA

It is proved that

RT-CGM is more

beneficial than SBGM


system on glycemic

control in type 1

diabetic patients:

systematic review and

meta-analysis of

randomized trials

in reducing HbA1c in

patients with type 1

diabetes. Further

studies are needed to

evaluate the efficacy

of this system in the

pediatric population,

especially in very

young children.

Glycemic control in

diabetic CAPD patients

assessed by

continuous glucose

monitoring system

(CGMS) 5 6 30 +IPA

It is proved that

CGMS appears to be

a valid and clinically

useful technology to

gain additional

insights into the

glycemic control of

diabetic CAPD

patients, when

compared to

available methods.

Nocturnal

hypoglycemia detected

with the Continuous

Glucose Monitoring

System in pediatric

patients with type 1

diabetes

5 5 25 +IPA

CGMS is a useful tool

to diagnose

asymptomatic

nocturnal

hypoglycemia.

Performance

Evaluation of the 5 5 25 +IPA

Under household

conditions, CGMS


MiniMed® Continuous

Glucose Monitoring

System During Patient

Home Use

and blood glucose

meter values have

good consistency.

Detailed blood sugar

information provided

by CGMS should

make the successful

management of

diabetes easier to

achieve.

A Comparative

Effectiveness Analysis

of Three Continuous

Glucose Monitors: The

Navigator, G4

Platinum, and Enlite

5 5 25 +IPA

A comprehensive

head-to-head-to-head

comparison of 3

CGMs revealed

marked differences in

both accuracy and

precision. All 3

devices had similar

reliability.

The Continuous

Glucose Monitoring

System Is Useful for

Detecting

Unrecognized

Hypoglycemias in

Patients with Type 1

and Type 2 Diabetes

but Is Not Better Than

Frequent Capillary

5 5 25 Balanced

The CGMS is useful

for detecting

unrecognized

hypoglycemias in

type 1 and type 2

diabetic subjects;

however, it is not

better than standard

capillary glucose

measurements for


Glucose Measurements

for Improving Metabolic

Control

improving metabolic

control of type 1

diabetic subjects,

regardless of the

therapeutic regimen.

A randomized

controlled pilot study of

continuous glucose

monitoring and flash

glucose monitoring in

people with Type 1

diabetes and impaired

awareness of

hypoglycaemia

5 5 25 +IPA

CGM more effectively

reduces time spent in

hypoglycaemia in

people with Type 1

diabetes and

impaired awareness

of hypoglycaemia

compared with flash

glucose monitoring.

Head-to-head

comparison of the

accuracy of Abbott

FreeStyle Libre and

Dexcom G5 mobile 6 6 36 +IPA

The data indicate that

both systems perform

safely and efficiently

but the G5 sensor

has greater accuracy

across all glucose

values except in

hypoglycaemia.

Hypoglycemic

Accuracy and Improved

Low Glucose Alerts of

the Latest Dexcom G4

Platinum Continuous

Glucose Monitoring

System

5 5 25 +IPA

RT-CGMS may

provide patients with

timely warning of

hypoglycemia before

the onset of cognitive

impairment, enabling

them to treat


themselves for

hypoglycemia with

fast-acting

carbohydrates and

prevent

neuroglycopenia

associated with very

low glucose levels.

Impact of Frequent and

Persistent Use of

Continuous Glucose

Monitoring (CGM) on

Hypoglycemia Fear,

Frequency of

Emergency Medical

Treatment, and SMBG

Frequency After One

Year

5 5 25 +IPA

“Almost daily” use of

CGM with the

Dexcom G4 system

reduced incidence of

emergency treatment

events and daily

SMBG utilization

among survey

respondents and a

trend toward reduced

hypoglycemia fear.

Nonadjunctive Use of

Continuous Glucose

Monitors for Insulin

Dosing: Is It Safe?

5 5 25 Balanced

Until the causes of

these sporadic, large

errors have been

identified, it would be

inappropriate to urge

users to regard the

device as safe for

insulin dosing without

confirmation.

Design and Clinical 6 6 36 +IPA An event-based


Evaluation of a Novel

Low-Glucose Prediction

Algorithm with

Mini-Dose Stable

Glucagon Delivery in

Post-Bariatric

Hypoglycemia

system can predict

and detect

hypoglycemia based

on continuous

glucose monitoring

(CGM) data, and it is

recommended to

provide low-dose

liquid glucagon for

the treatment of

postweight-loss

hypoglycemia (PBH)

as a complication of

weight-loss surgery.

Hypoglycemic

symptoms in the

absence of diabetes:

Pilot evidence of clinical

hypoglycemia in young

women

6 6 36 Balanced

CGMS can be used

to verify the

consistency between

hypoglycemic

symptoms and

hypoglycemic values.

The use of real time

continuous glucose

monitoring or flash

glucose monitoring in

the management of

diabetes: A consensus

view of Italian diabetes

experts using the

Delphi method

5 5 25 +IPA

Most experts

consider rtCGM and

FGM as two separate

categories of

interstitial

subcutaneous fluid

(ISF) sensing

technologies, and see

them as superior to


SMBG. Furthermore,

there is strong

consensus that

rtCGM and FGM

reduce hypoglycemia

risk, increase the

amount of time in the

target glucose range

and augment

treatment

satisfaction.

Retrofitting Real-Life

Dexcom G5 Data 5 5 25 +IPA

Improved algorithm

can improve the

accuracy of CGMS

4.6. Analysis of the clinical data

4.6.1. Requirement on safety (MDD ER1)

A series of verification evaluations were conducted to assess the safety and

performance of the devices. Studies performed were identified on the basis of risk

analysis activities and testing of the product’s performance. Specific the following

variable and attribute characteristics were evaluated and the residual risks were

reduced to acceptable level:

• Biocompatibility: biocompatibility evaluation was conducted according to EN ISO

10993 series standards and passed all relevant tests.

• Operational/Information: Indication/contraindication, warning and direction for

use were presented in user manual.

• Electro/magnetic hazards: electronic performance/safety and EMC were


evaluated based on applicable EN 60601-1 series standards.

• Radiation hazards: Risk of retinal injury was reduced by adequate warning given

in user manual.

4.6.2. Requirement on acceptable benefit/risk profile (MDD ER1)

Risk management process was implemented as addressed in Risk Management Report

#. I3/WJ-XT-FXFX-01.The risks associated with the intended purpose are minimized

and acceptable when weighed against the benefits to the patient and are compatible

with a high level of protection of health and safety.

IFU has been established based on the MDD ER1 Sec. 13 and clinical data from

literature searching, related information about contraindication, warnings, precautions

and instructions were adequately given, e.g. indication, contraindication, application

method and relevant warnings, and so on.

4.6.3. Requirement on performance (MDD ER3)

The Continuous Glucose Monitoring Systems is intended for continuous or periodic

recording of interstitial fluid glucose levels in adult patients with diabetes aged 18 or

older. The system is designed for patients to use at home and in medical institutions,

and the main findings of the clinical studies are presented in Appendix 1.

4.6.4. Requirement on acceptability of side-effects (MDD ER6)

Articles Pertaining to Potential Complications/Side-effect were reviewed and analyzed

as presented in Appendix 1.

Side-effects and complications identified from literature search were reviewed and

summarized.

Adequate information was given in IFU to minimize the risks.

According to risk management output, the overall residual risks were within acceptable

level.


4.6.5 Postmarket surveillance Data

To supplement the literature review, an assessment of postmarket surveillance data via

review of the U.S. Food and Drug Administration’s Manufacturer and User Facility

Device Experience (MAUDE) database for similar products with same product code

was conducted.

The database was searched for a ten-years’ period starting in Jan 01 2008 through Dec

31, 2017 to identify reportable events associated with competitor products that are

similar in intended use and function to the CONTINUOUS GLUCOSE MONITORING

SYSTEMS identified within this CER.


These reportable events are mainly due to: Wireless Communication Problem,

Imprecision, Retraction Problem and Use of Device Problem, which are all indicated in

the adverse events in the user manual, as well as evaluated and controlled in the risk

management process.

We considered these events and their reasons during the design and manufacturing


process of the devices to avoid or decrease the probability of these events occurred.

We implemented the corresponding measures to control these potential hazards, and it

has been proved that the control measures are effective.

Problem 1: Wireless Communication Problem

Control measures: WJ-XT-FXFX-01 Risk management file, H15: Failure of connection

between sensor and transmitter. H16: The transmitter and App cannot be connected

normally. H22: Device may interfere with other equipment when it is working.

Problem 2: Imprecision

Control measures: WJ-XT-FXFX-01 Risk management file, H9: The blood sugar level

tested is not accurate. H10: The software is abnormal, the blood glucose level is not

accurate. H11: Forgetting calibration or incorrect calibration data results in inaccurate

blood glucose values. H12: Life expectancy, sensor coating enzyme inactivation or

transmitter battery loss lead to inaccurate blood glucose values. H14: Equipment was

used by untrained personnel

Problem 3: Retraction Problem

Control measures: WJ-XT-FXFX-01 Risk management file, H8: When the sensor is

implanted, the operation method is wrong. H27: Incomplete IFU, cause the operator

cannot use the product correctly

Problem 4: Use of Device Problem

Control measures: WJ-XT-FXFX-01 Risk management file, H32: Menu prompt is not

clear, ambiguous, or the user fails to understand the content of the menu correctly. H33:

The prompt tone is not clear. H34: The menu is not clearly displayed. H35: Unclear

Prompt or path

5. Conclusions

The limitations of the study are that only published literature is collected and

unpublished documents about negative result cannot be examined. The collected


literature mainly concerns the assessment of the treatment efficacy and safety.

Base on evaluation on identification of data, pre-clinical evaluation, literature,

post-market surveillance and risk analysis, the evaluation conclusion is:

The safety and performance of the device from the evaluation with respect to the

intended use of the device as claimed have been established, and the risks associated

with the use of the device are acceptable when weighed against the Benefits to the

patient.

The risk/ benefit analysis shows that the benefits when using the device outweigh the

risks. Product is safety and effective in clinical use as system for human being.

The plan for Post-Market Clinical Follow-Up (PMCF) for device will include monitoring of

information such as complaints, adverse events, investigation reports, and possible

off-label use and user trends on an on-going basis in accordance with company

procedures. Further clinical evaluation will be documented periodically based on

observed trends or new emerging risks.

6. Date of the next clinical evaluation

The clinical evaluation is actively updated:

• when the manufacturer receives new information from PMS that has the potential to

change the current evaluation;

• if no such information is received, then

- At least annually if the device carries significant risks or is not yet well established;

or

- Every 2 years if the device is not expected to carry significant risks and is well

established, a justification should be provided.

7. Dates and signatures

Date of Signature:


Name of Author: Signature

Name of Author: Signature

8. Qualification of the responsible evaluators

MISS.WANG Xiaoyu, Graduated from China Pharmaceutical University, now working in

Infinovo Medical CO., LTD.,5 years’ medical experience.

MR XIAO linchun, now working in Infinovo Medical CO., LTD., over 10 years’ medical

experience.


References

1. Efficacy and safety comparison of continuous glucose monitoring and

self‑monitoring of blood glucose in type 1 diabetes, Piotr Wojciechowski1,

Przemysław Ryś1, Anna Lipowska2,3, Magdalena Gawęska1, Maciej T. Małecki3,4

2. Beneficial effect of real-time Continuous Glucose Monitoring Systems on glycemic

control in type 1 diabetic patients systematic review and meta-analysis of

randomized trials, A Szypowska, A Ramotowska, K Dz˙ygało and D Golicki1

3. Glycemic control in diabetic CAPD patients assessed by Continuous Glucose

Monitoring Systems (CGMS), JENNIFER MARSHALL, PETER JENNINGS,

ADRIAN SCOTT, RICHARD J. FLUCK, and CHRISTOPHER W. MCINTYRE

4. Nocturnal hypoglycemia detected with the Continuous Glucose Monitoring Systems

in pediatric patients with type 1 diabetes, Francine Ratner Kaufman, MD, Juliana

Austin, MD, Aaron Neinstein, BA, Lily Jeng, BA, Mary Halvorson, RN, MSN, CDE,

Debra J. Devoe, MD, and Pisit Pitukcheewanont, MD

5. Performance Evaluation of the MiniMed® Continuous Glucose Monitoring Systems

During Patient Home Use, TODD M. GROSS, Ph.D.,1 BRUCE W. BODE, M.D.,2

DANIEL EINHORN, M.D.,3 DAVID M. KAYNE, M.D.,4 JOHN H. REED, M.D.,5 NEIL

H. WHITE, M.D.,and JOHN J. MASTROTOTARO, Ph.D.1

6. A Comparative Effectiveness Analysis of Three Continuous Glucose Monitors: The

Navigator, G4 Platinum, and Enlite. Edward R. Damiano, PhD1, Katherine McKeon,

MEng1, Firas H. El-Khatib, PhD1, Hui Zheng, PhD2, David M. Nathan, MD3, and

Steven J. Russell, MD, PhD

7. The Continuous Glucose Monitoring Is Useful for Detecting Unrecognized

Hypoglycemias in Patients With Type 1 and Type 2 Diabetes but Is Not Better Than

Frequent Capillary Glucose Measurements for Improving Metabolic, ANA CHICO,

MD, PHD,PABLO VIDAL-R IOS, MD, PHD,MONTSERRAT SUBIR`A, NPANNA

NOVIALS, MD, PHD

8. A Practical Approach to Using Trend Arrows on the Dexcom G5 CGM System to

Manage Children and Adolescents With Diabetes. Laffel LM, Aleppo G, Buckingham


BA, Forlenza GP, Rasbach LE, Tsalikian E, Weinzimer SA, Harris DR

9. A randomized controlled pilot study of continuous glucose monitoring and flash

glucose monitoring in people with Type 1 diabetes and impaired awareness of

hypoglycaemia. Reddy M, Jugnee N, El Laboudi A, Spanudakis E, Anantharaja S,

Oliver N

10. Head-to-head comparison of the accuracy of Abbott FreeStyle Libre and Dexcom

G5 mobile. Boscari F, Galasso S, Acciaroli G, Facchinetti A, Marescotti MC, Avogaro

A, Bruttomesso

11. Hypoglycemic Accuracy and Improved Low Glucose Alerts of the Latest Dexcom G4

Platinum Continuous Glucose Monitoring Systems. Peyser TA, Nakamura K, Price D,

Bohnett LC, Hirsch IB, Balo A

12. Impact of Frequent and Persistent Use of Continuous Glucose Monitoring (CGM) on

Hypoglycemia Fear, Frequency of Emergency Medical Treatment, and SMBG

Frequency After One Year. Chamberlain JJ, Dopita D, Gilgen E, Neuman A.

13. Nonadjunctive Use of Continuous Glucose Monitors for Insulin Dosing: Is It Safe?

Shapiro AR

14. Design and Clinical Evaluation of a Novel Low-Glucose Prediction Algorithm with

Mini-Dose Stable Glucagon Delivery in Post-Bariatric Hypoglycemia

15. Hypoglycemic symptoms in the absence of diabetes: Pilot evidence of clinical

hypoglycemia in young women

16. The use of real time continuous glucose monitoring or flash glucose monitoring in

the management of diabetes: A consensus view of Italian diabetes experts using the

Delphi method

17. Retrofitting Real-Life Dexcom G5 Data. Favero SD, Facchinetti A, Sparacino G,

Cobelli C


Appendix 1: Main Study Findings and Authors’ Conclusions

Article Experimental Design (or

Article Description)

Subjects Evaluated Outcomes/Relevant Findings Level of

Evidence

Suitability and

Contribution

Efficacy and safety

comparison of continuous

glucose monitoring and

selfmonitoring of blood

glucose in type 1 diabetes

Based on a systematic review

and meta‑analysis, we aimed

to assess the efficacy and

safety of various CGM

systems compared with

SMBG

We searched major medical

databases up to June 2011

for randomized controlled

trials comparing CGM and

SMBG in type 1 diabetes.

Studies of at least 12‑week

duration were included.

CGM, partcicularly its real‑time

system, has a favorable effect on

glycemic control and decreases

the incidence of hypoglycemic

episodes in both adult and

pediatric patients with type 1

diabetes.

Level I evidence

D2, A1, P1, R1

T1, O1, F1, S1,

C1

Beneficial effect of

real-time continuous

glucose monitoring

system on glycemic

control in type 1 diabetic

patients: systematic

review and meta-analysis

The aimof this studywas to

explore the potential

beneficial effects of the use of

RT-CGMon diabetes

management compared with

self blood glucose

measurement (SBGM) in

patients with type 1 diabetes

mellitus (T1DM), bymeans of

a systematic review

MEDLINE, EMBASE, and

the Cochrane Library were

searched through by two

independent investigators

for RCTs concerning the

use of RT-CGM in patients

with T1DM.

RT-CGM is more beneficial than

SBGM in reducing HbA1c in

patients with type 1 diabetes.

Further studies are needed to

evaluate the efficacy of this

system in the pediatric

population, especially in very

young children.

Level I evidence

D2, A1, P1, R1

T1, O1, F1, S1,

C1





Evidence

Suitability and

Contribution

of randomized trials andmeta-analysis of

randomized controlled trials

(RCTs).

Glycemic control in

diabetic CAPD patients

assessed by continuous

glucose monitoring

system (CGMS)

The aims of this study were

to investigate the use of the

continuous glucose

monitoring system (CGMS) to

assess overall 24-hour

glycemic control and the

effects of both nonglucose

containing and more

biocompatible alternative

peritoneal dialysis solutions in

insulin-treated continuous

ambulatory peritoneal dialysis

(CAPD) patients.

We studied eight patients

with ESRF. All patients had

been treated with CAPD as

their only dialysis modality.

CGMS appears to be a clinically

useful tool to gain additional

insights into the glycemic control

of diabetic CAPD patients.

Level ǁ evidence

D2, A1, P2, R1

T1, O1, F1, S1,

C1

Nocturnal hypoglycemia

detected with the

Continuous Glucose

To use the Continuous


(CGMS, MiniMed, Sylmar,

Calif) to determine if bedtime

blood glucose levels were

Patients (n = 47, 18 boys,

mean age 11.8 ± 4.6 years)

with type 1 diabetes used

CGMS for 167 nights. Data

were analyzed for glucose

Nocturnal hypoglycemia is

frequent, of long duration,

associated with bedtime glucose

values ≤100 to 150 mg/dL, and

predominately in the early part of

Level ǁ evidence

D2, A1, P2, R2

T1, O1, F1, S2,





Evidence

Suitability and

Contribution

Monitoring System in

pediatric patients with

type 1 diabetes

associated with the

occurrence of nocturnal

hypoglycemia

≤40 or ≤50 mg/dL,

comparing bedtime blood

glucose levels of ≤100

or >100 mg/dL and ≤150

or >150 mg/dL.

the night. CGMS is a useful tool

to diagnose asymptomatic

nocturnal hypoglycemia.

C1

Performance Evaluation

of the MiniMed®

Continuous Glucose

Monitoring System During

Patient Home Use

The present study evaluates

the performance of the

MiniMed® Continuous


(CGMS) in patients with

diabetes during home use.

Performance data from the

first 135 uses of the CGMS

reported to the device

manufacturer have been

summarized.

These results demonstrate the

reliable and accurate

performance of the CGMS under

conditions of outpatient use.

Level ǁ evidence

D2, A1, P1, R1

T1, O1, F1, S1,

C1

A Comparative

Effectiveness Analysis of

Three Continuous

Glucose Monitors: The

Navigator, G4 Platinum,

and Enlite

The effectiveness and safety

of continuous glucose

monitors (CGMs) is

dependent on their accuracy

and reliability. The objective

of this study was to compare

Twenty-four subjects (12

adults) with type 1 diabetes

each participated in one

48-hour closed-loop BG

control experiment. Venous

plasma glucose (PG)

measurements obtained

every 15 minutes (4657

values) were paired in time

with corresponding CGM

Results: The Navigator and G4

Platinum (G4) had the best

overall accuracy, with an

aggregate mean absolute relative

difference (MARD) of all paired

points of 12.3 ± 12.1% and 10.8 ±

9.9%, respectively. Both had

lower MARDs of all paired points

than Enlite (17.9 ± 15.8%, P

< .005). Very large errors

Level ǁ evidence

D2, A1, P1, R1

T1, O1, F1, S1,

C1





Evidence

Suitability and

Contribution

3 CGMs in adult and pediatric

subjects with type 1 diabetes

under closed-loop

blood-glucose (BG) control.

glucose (CGMG)

measurements obtained

from 3 CGMs (FreeStyle

Navigator, Abbott Diabetes

Care; G4 Platinum,

Dexcom; Enlite, Medtronic)

worn simultaneously by

each subject.

(MARD > 50%) were less

common with the G4 (0.5%) than

with the Enlite (4.3%, P = .0001)

while the number of very large

errors with the Navigator (1.4%)

was intermediate between the G4

and Enlite (P = .1 and P = .06,

respectively). The average MARD

for experiments in adolescent

subjects were lower than in adult

subjects for the Navigator and

G4, while there was no difference

for Enlite. All 3 devices had

similar reliability. Conclusions:

A comprehensive

head-to-head-to-head

comparison of 3 CGMs revealed

marked differences in both

accuracy and precision. The

Navigator and G4 were found to

outperform the Enlite in these

areas





Evidence

Suitability and

Contribution

The Continuous Glucose

Monitoring System Is

Useful for Detecting

Unrecognized

Hypoglycemias in

Patients with Type 1 and

Type 2 Diabetes but Is

Not Better Than Frequent

Capillary Glucose

Measurements for

Improving Metabolic

Control

To evaluate whether the

Continuous Glucose

Monitoring Systems (CGMS;

MiniMed, Sylmar, CA) is

useful for investigating the

incidence of unrecognized

hypoglycemias in type 1 and

type 2 diabetic patients and

for improving metabolic

control in type 1 diabetic

patients.

A total of 70 diabetic

subjects (40 type 1 and

30 type 2 subjects) were

monitored using the CGMS.

The CGMS is useful for detecting

unrecognized hypoglycemias in

type 1 and type 2 diabetic

subjects; however, it is not better

than standard capillary glucose

measurements for improving

metabolic control of type 1

diabetic subjects, regardless of

the therapeutic regimen.

Level ǁ evidence

D2, A1, P1, R1

T1, O1, F1, S1,

C1

A randomized controlled

pilot study of continuous

glucose monitoring and

flash glucose monitoring

in people with Type 1

diabetes and impaired

awareness of

hypoglycaemia

Hypoglycaemia in Type 1

diabetes is associated with

mortality and morbidity,

especially where awareness

of hypoglycaemia is impaired.

Clinical pathways for access

to continuous glucose

monitoring (CGM) and flash

glucose monitoring

technologies are unclear. We

A randomized, non-masked

parallel group study was

undertaken. Adults with

Type 1 diabetes using a

multiple-dose

insulin-injection regimen

with a Gold score of ≥ 4 or

recent severe

hypoglycaemia were

recruited. Following 2 weeks

RESULTS:

CONCLUSION:

CGM more effectively reduces

time spent in hypoglycaemia in

people with Type 1 diabetes and

impaired awareness of

hypoglycaemia compared with

flash glucose monitoring

Level ǁ evidence

D2, A1, P2, R1

T1, O1, F1, S1,

C1





Evidence

Suitability and

Contribution

assessed the impact of CGM

and flash glucose monitoring

in a high-risk group of people

with Type 1 diabetes.

of blinded CGM, they were

randomly assigned to CGM

(Dexcom G5) or flash

glucose monitoring (Abbott

Freestyle Libre) for 8 weeks.

The primary outcome was

the difference in time spent

in hypoglycaemia (below 3.3

mmol/l) from baseline to

endpoint with CGM versus

flash glucose monitoring.

Head-to-head

comparison of the

accuracy of Abbott

FreeStyle Libre and

Dexcom G5 mobile

The aim of this study was to

compare the performance of

FSL and DG5M. Differently

from the previous study, here

both sensors were used

according to their

manufacturer specified

Recently, we published in

Nutrition Metabolism

Cardiovascular Disease an

article comparing the

accuracy of flash glucose

monitoring Freestyle Libre

(FSL, Abbott Diabetes Care,

Our data indicate that both

systems perform safely and

efficiently but the DG5M sensor

has greater accuracy across all

glucose values except in

hypoglycaemia. Furthermore, as

shown before , Libre’s accuracy

Level ǁ evidence

D2, A1, P1, R2

T1, O1, F1, S1,

C2





Evidence

Suitability and

Contribution

life times, patients received

only one breakfast test and

used a glucometer

independently of the devices

to avoid bias in assessing the

accuracy at home.

Alameda, CA; wear lifetime

14 days) with that of the

continuous glucose

monitoring device Dexcom

G4 Platinum (DG4P,

Dexcom, San Diego, CA)

[3]. After the completion of

that study, using the same

methodology, we compared

the accuracy of FSL with

that of Dexcom G5 Mobile

(DG5M; wear lifetime 7

days), the most recent

sensor produced by

Dexcom Inc.

decreases between days 11 and

14, an important finding for

patients, especially when using

the sensor as non-adjunctive

device continuously for 14 days





Evidence

Suitability and

Contribution

Hypoglycemic Accuracy

and Improved Low

Glucose Alerts of the

Latest Dexcom G4

Platinum Continuous

Glucose Monitoring

System

Accuracy of continuous

glucose monitoring (CGM)

devices in hypoglycemia has

been a widely reported

shortcoming of this

technology. We report the

accuracy in hypoglycemia of

a new version of the Dexcom

(San Diego, CA) G4 Platinum

CGM system (software 505)

and present results regarding

the optimum setting of CGM

hypoglycemic alerts.

CGM values were

compared with YSI analyzer

(YSI Life Sciences, Yellow

Springs, OH)

measurements every

15 min. We reviewed the

accuracy of the CGM

system in the hypoglycemic

range using standard

metrics. We analyzed the

time required for the CGM

system to detect

biochemical hypoglycemia

(70 mg/dL) compared with

the YSI with alert settings at

70 mg/dL and 80 mg/dL. We

also analyzed the time

between the YSI value

crossing 55 mg/dL, defined

as the threshold for

cognitive impairment due to

hypoglycemia, and when

CONCLUSIONS:

Use of an 80 mg/dL threshold

setting for hypoglycemic alerts on

the G4 Platinum (software 505)

may provide patients with timely

warning of hypoglycemia before

the onset of cognitive impairment,

enabling them to treat themselves

for hypoglycemia with fast-acting

carbohydrates and prevent

neuroglycopenia associated with

very low glucose levels.

Level ǁ evidence

D2, A1, P2, R1

T1, O1, F1, S1,

C2





Evidence

Suitability and

Contribution

the CGM system alerted for

hypoglycemia.

Impact of Frequent and

Persistent Use of

Continuous Glucose

Monitoring (CGM) on

Hypoglycemia Fear,

Frequency of Emergency

Medical Treatment, and

SMBG Frequency After

One Year

We assessed the impact of

"almost daily" use of

continuous glucose

monitoring (CGM) in adults

with type 1 diabetes who had

at least 1 year of CGM

experience

In this single-center survey,

we utilized a 16-item

questionnaire to assess

changes hypoglycemia fear,

incidence of emergency

medical treatment and

utilization of self-monitoring

of blood glucose (SMBG)

before and after 1 year of

CGM use. Participation was

restricted to individuals who

used the same brand of

CGM system to avoid

confounding responses due

to differences between

commercial devices.

Participants were recruited

on an "as-seen" basis from

a major, urban internal

medicine clinic and

"Almost daily" use of CGM with

the Dexcom G4 system reduced

incidence of emergency

treatment events and daily SMBG

utilization among survey

respondents and a trend toward

reduced hypoglycemia fear. This

may indicate cost savings in

reduction of emergency medical

intervention and likely improved

quality of life without increasing

safety concerns related to

hypoglycemia.

Level ǁ evidence

D2, A1, P1, R1

T1, O1, F1, S1,

C1





Evidence

Suitability and

Contribution

associated diabetes

education center. The

questionnaire was

completed during the clinic

visit. Responses to the

survey were analyzed by

standard descriptive

statistics.

Nonadjunctive Use of

Continuous Glucose

Monitors for Insulin

Dosing: Is It Safe?

With the increasing accuracy

of continuous glucose

monitors (CGM) have come

calls for the Food and Drug

Administration (FDA) to label

these devices as safe for

nonadjunctive dosing of

insulin. However, there is

evidence that these devices

are subject to sporadic,

unpredictable, large errors.

A text analysis of reports to

the FDA MAUDE database

since 2015 reveals over 25

000 complaints of CGM

sensor inaccuracy, with

instances directly leading to

serious outcomes. These

new data were not

considered at a recent FDA

Advisory Panel meeting that

voted to approve Dexcom

G5 relabeling for

nonadjunctive use.

Social media is another source of

surveillance data providing

evidence of large CGM

inaccuracies in real-world use.

We need to improve safety

procedures, not remove them.

CGMs offer unique information

and alerts for managing diabetes,

but the issue is not whether they

are better than other approaches

to monitoring glucose, but how

they can be best used in

conjunction with devices that offer

the confirmatory readings needed

Level III

evidence

D2, A1, P1, R1

T1, O1, F2, S1,

C1





Evidence

Suitability and

Contribution

for patient safety

Design and Clinical

Evaluation of a Novel

Low-Glucose Prediction

Algorithm with Mini-Dose

Stable Glucagon Delivery

in Post-Bariatric

Hypoglycemia

Postbariatric hypoglycemia

(PBH) is a complication of

bariatric surgery with limited

therapeutic options. We

developed an event-based

system to predict and detect

hypoglycemia based on

continuous glucose monitor

(CGM) data and recommend

delivery of minidose liquid

glucagon.

We performed an iterative

development clinical study

employing a novel glucagon

delivery system: a Dexcom

CGM connected to a

Windows tablet running a

hypoglycemia prediction

algorithm and an Omnipod

pump filled with an

investigational stable liquid

glucagon formulation. Meal

tolerance testing was

performed in seven

participants with PBH and

history of neuroglycopenia.

Glucagon was administered

when hypoglycemia was

predicted. Primary outcome

measures included the

safety and feasibility of this

system to predict and

Preliminary results indicate that

our event-based automatic

monitoring algorithm successfully

predicted likely hypoglycemia.

Minidose glucagon therapy was

well tolerated, without prolonged

or severe hypoglycemia, and

without rebound hyperglycemia.

Level III

evidence

D2, A1, P1, R1

T1, O1, F1, S2,

C1





Evidence

Suitability and

Contribution

prevent severe

hypoglycemia. Secondary

outcomes included

hypoglycemia prediction by

the prediction algorithm,

minimization of time below

hypoglycemia threshold

using glucagon, and

prevention of rebound

hyperglycemia.

Hypoglycemic symptoms

in the absence of

diabetes: Pilot evidence

of clinical hypoglycemia

in young women

Clinical visits of non-diabetic

patients reporting

hypoglycemic symptoms are

common in endocrinology

practices, but remain

understudied and lack clinical

definition and evidence-based

recommendations for

diagnosis or treatment. Our

goal was to pilot test the

concordance of hypoglycemic

symptoms with low glucose

We recruited eight

individuals who reported

regularly experiencing

symptoms consistent with

hypoglycemia to wear a

blinded Dexcom continuous

glucose monitor and report

symptoms for seven days.

We excluded individuals with

diabetes or other known

causes of hypoglycemia or

similar symptoms.

Individuals with hypoglycemic

symptoms in the absence of

diabetes experience clinical

hypoglycemia, indicating the need

to understand the etiology,

behavioral responses, and other

health risks that might be

associated with this understudied

condition.

Level IV

evidence

D2, A1, P2, R1

T1, O1, F2, S2,

C1





Evidence

Suitability and

Contribution

values in young non-diabetic

individuals.

The use of real time

continuous glucose

monitoring or flash

glucose monitoring in the

management of diabetes:

A consensus view of

Italian diabetes experts

using the Delphi method

the use of continuous glucose

monitoring (CGM) systems has

been limited, but is now

rapidly increasing, including

the so-called real-time CGM

(rtCGM) and the intermittently

viewed CGM (iCGM), also

called Flash Glucose

Monitoring (FGM). These

technologies overcome many

of the limitations of

self-monitoring of blood

glucose (SMBG) by fingerprick

and allow to go beyond

HbA1c to check glucose

control in diabetes. However,

standardized protocols for

applying and interpreting

rtCGM and FGM data are

lacking

In this paper, we delineate a

consensus amongst Italian

diabetes physicians on the

attributes of rtCGM and FGM

technologies, and introduce

a consistent approach for

their use by Italian healthcare

professionals.

Most experts consider rtCGM and

FGM as two separate categories of

interstitial subcutaneous fluid (ISF)

sensing technologies, and see

them as superior to SMBG.

Furthermore, there is strong

consensus that rtCGM and FGM

reduce hypoglycemia risk, increase

the amount of time in the target

glucose range and augment

treatment satisfaction. However,

there is still no agreement on the

indication of the FGM for subjects

who suffer asymptomatic

hypoglycemia. Consensus on the

role of education in initiating and

optimizing use of rtCGM/FGM and

about the interpretation of glucose

trends was near unanimous,

whereas no consensus was

Level IV

evidence

D2, A1, P2, R1

T1, O1, F2, S2,

C2





Evidence

Suitability and

Contribution

reached on the statement that

there are no disadvantages/risks of

rtCGM/FGM.

Retrofitting Real-Life

Dexcom G5 Data

We proposed in 2014 a

retrofitting algorithm to

retrospectively increase the

accuracy of continuous

glucose monitoring (CGM)

data by using some blood

glucose (BG) measurements.

The method proved effective

on Dexcom SEVEN Plus

when about 10 highly

accurate YSI

measurements/session were

available. In this study, we

test the method on Dexcom

G5 sensor in a more realistic

setup, where only five

capillary BG measurements

(self-monitoring blood

glucose [SMBG]) per

The algorithm was tested in

51 adults and 46

adolescents studied for 7

days with Dexcom G5. Each

patient also underwent an

∼12-h hospital admission

where frequent SMBG and

YSI measurements were

collected. First, five SMBGs

per 12-h session were used

to retrofit the CGM. Then,

we varied the number of

SMBGs provided to the

method from 2 to 10 per

12-h session.

RESULT:

Retrofitted CGM traces with five

SMBGs per 12-h session have

lower mean absolute difference

than original CGM, reduced from

16.2 to 10.7 mg/dL (P < 0.001) in

adults and from 17.6 to

11.5 mg/dL (P < 0.001) in

adolescents, and mean absolute

relative difference is reduced

from 9.0% to 6.4% (P < 0.001) in

adults and from 10.3% to 6.8%

(P < 0.001) in adolescents.

Reducing the number of BG

measurements reduces

improvement in the accuracy

from >30% with 10 SMBGs per

12-h session to <16% with 2

SMBGs/day.

Level II evidence

D2, A1, P1, R1

T1, O1, F1, S1,

C1





Evidence

Suitability and

Contribution

12 h-session are available.

Furthermore, we investigate

how accuracy is affected by

the number of BG

measurements

CONCLUSION:

The retrofitting method

retrospectively improves the

accuracy of CGM data, even if

applied to one of the most

accurate CGM sensors currently

available on the market.

Clinical Evaluation Of Continuous Glucose Monitoring Systems

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