REGULATORY PROFILEGLUCOSE SELF-MONITORING TOOLSOCTOBER 2021

Regulatory Profile for Glucose
Self-monitoring Tools

OCTOBER 2021

Compiled by Robyn Meurant, NSF Health Sciences, with contributions from Guido Freckmann
and Stefan Pleus, Institute for Diabetes Technology

Disclaimer: The ACCISS Study is supported by The Leona M. and Harry B. Helmsley Charitable Trust.
The analysis included in this report is that of the authors alone and does not necessarily reflect theviews of the Helmsley Charitable Trust. All references and conclusions are intended for educational
and informative purposes and do not constitute an endorsement or recommendation from theHelmsley Charitable Trust.
Regulatory Profile for Glucose Self-monitoring Tools 1

Table of Contents
Abbreviations, definitions and descriptions ................................................................................. 5
1.

INTRODUCTION ...................................................................................................................... 8

2.

DEVICES FOR SELF-MONITORING OF DIABETES .............................................................. 10

3.

2.1.

Self-monitoring blood glucose systems - SMBGs....................................................... 10

2.2.

Continuous glucose monitoring systems - CGMs ...................................................... 10

AN OVERVIEW OF THE REGULATION OF MEDICAL DEVICES .......................................... 13
3.1.

Definitions of medical devices and IVDs ..................................................................... 13

3.1.1.

Medical device ................................................................................................... 13

3.1.2.

IVD medical device ............................................................................................ 14

3.1.3.

Devices ............................................................................................................... 14

3.2.

Internationally agreed regulatory framework .............................................................. 14

3.2.1.

Evolution of regulation of medical devices and IVDs compared with medicines
14

3.2.2.

The GHTF model for regulation of medical devices and IVDs ....................... 15

3.3.

Critical elements of the GHTF regulatory model......................................................... 16

3.3.1.

Conformity Assessment .................................................................................... 16

3.3.2.

Risk classification .............................................................................................. 17

3.3.3.

Technical documentation.................................................................................. 17

3.3.4.

Use of standards ................................................................................................ 18

3.3.5.

Unique Device Identifier (UDI) ........................................................................... 18

3.4.

Global adoption of the GHTF regulatory model .......................................................... 20

3.5.

Implementation of medical devices and IVD regulation ............................................ 20

3.6.

WHO model regulatory framework for medical devices including IVDs ................... 22

3.7.

Global progress in implementing medical device regulation ..................................... 22

3.8. Roles and responsibilities within a regulatory system: manufacturers, national
regulatory authorities (NRAs) and Conformity Assessment Bodies (CABs) ....................... 23
4.

REGULATION OF SELF-MONITORING DEVICES FOR DIABETES ...................................... 25
4.1.

The regulation of devices in the USA and the EU ........................................................ 25

4.1.1.

Comparison of US and EU regulation ................................................................... 25

Regulatory Profile for Glucose Self-monitoring Tools 2

4.1.2.
Comparison of the US and EU regulation of self-monitoring blood glucose
devices (SMBGs) .................................................................................................................. 26
4.1.3.
Comparison of the US and EU regulation of Continuous Glucose Monitoring
systems (CGMs) ................................................................................................................... 31
4.1.4.
4.2.

High level overview of regulation of self-monitoring devices by China and Tanzania
37

4.2.1.

China ................................................................................................................... 37

4.2.2.

Tanzania ............................................................................................................. 39

4.3.

5.

Comparison of the regulatory mechanisms .................................................... 36

WHO Prequalification .................................................................................................... 40

4.3.1.

The PQ Procedure .............................................................................................. 40

4.3.2.

Abridge PQ procedure ....................................................................................... 41

CHALLENGES ASSOCIATED WITH THE USE OF SMBGS AND CGMS ............................. 42
5.1.

Access to accurate devices .......................................................................................... 42

5.2.

Adverse events reported for the use of self-monitoring devices............................... 42

5.2.1.

Adverse event reporting .................................................................................... 42

5.2.2.

Agência Nacional de Vigilância Sanitária (ANVISA) actions .......................... 45

5.3.

Substandard and counterfeit devices .......................................................................... 45

6. ANALYSIS OF THE EFFECTIVENESS OF CURRENT GUIDANCE FOR DEVICEDEVELOPMENT AND ASSESSMENT ........................................................................................... 46

7.

6.1.

Self-monitoring blood glucose devices- SMBGs ......................................................... 46

6.2.

Continuous glucose monitoring systems - CGMs ...................................................... 50

DISCUSSION ......................................................................................................................... 52
7.1.

Tools for Improvement: General .................................................................................. 52

7.1.1.

Verification of performance by the regulatory authority ................................. 52

7.1.2.

Standardised reference method ....................................................................... 53

7.1.3.

Clinical impact assessment .............................................................................. 54

7.1.4.

Adverse event reporting .................................................................................... 56

7.1.5.

Substandard and falsified devices ................................................................... 56

7.1.6.

Specific requirements in LMICs ........................................................................ 56

7.2.

SMBGs ............................................................................................................................ 57

7.2.1.
7.3.

Adjusted protocols ................................................................................................ 57

CGMs .............................................................................................................................. 58

7.3.1.

Metrological traceability .................................................................................... 58
Regulatory Profile for Glucose Self-monitoring Tools 3

8.

7.3.2.

Study procedures ............................................................................................... 59

7.3.3.

Other requirements ............................................................................................ 59

RECOMMENDATIONS .......................................................................................................... 60
8.1.

Effective implementation of regulations ..................................................................... 60

8.2.

Enhanced post-market activities by manufacturers ................................................... 60

8.3. Understanding the critical impact of temperature and humidity on performance of
SMBG strips .............................................................................................................................. 60
8.4.

LMIC activities in the absence of strong in-country regulation ................................. 61

8.4.1.

Survey of quality of self-management devices on the LMIC market ............. 61

8.4.2.

Recognition and Reliance .................................................................................. 61

8.4.3.

Pre-distribution QC activities............................................................................. 61

8.4.4.

Assuring temperature-controlled supply of SMBG strips ............................... 61

8.5.

UDI and Increased stakeholder awareness ................................................................. 61

8.6.

Enhancing awareness of regulatory support in people living with diabetes ............. 62

8.7.

Reference Institutions ................................................................................................... 62

9. APPENDIX 1. REGULATION OF DEVICES BY THE UNITED STATES OF AMERICA FOOD
AND DRUG ADMINISTRATION ..................................................................................................... 63
9.1.

Overview of regulation of devices within FDA ............................................................. 63

9.1.1.
9.2.

FDA regulation overview of SMBGs ............................................................................. 64

9.2.1.
9.3.

10.

Pre-market notification 510(k) .......................................................................... 63

Regulatory requirements — general controls for Class II devices .................. 65

FDA regulation of Continuous Glucose Monitoring Systems (CGMs)....................... 65

9.3.1.

FDA Regulation Overview of CGMs .................................................................. 65

9.3.2.

Regulatory Requirements .................................................................................. 67

APPENDIX 2. REGULATION OF DEVICES IN THE EU ...................................................... 68

10.1.

The regulatory framework in the EU ......................................................................... 68

10.2.

Regulation of Self-Monitoring Blood Glucose Test Systems (SMBGs) in the EU . 73

10.3.

Regulation of Continuous Glucose Monitoring Systems (CGMs) in the EU .......... 74

Acknowledgments
This report was compiled by Robyn Meurant, NSF Health Sciences, with contributions from Guido
Freckmann and Stefan Pleus, Institute for Diabetes Technology, with support from the Foundation for
Innovative New Diagnostics (FIND) and Health Action International (HAI). The report was undertaken

Regulatory Profile for Glucose Self-monitoring Tools 4

as part of HAI’s Addressing the Challenge and Constraints of Insulin Sources and Supply (ACCISS)
Study.

Abbreviations, definitions and descriptions
AHWP

Asian Harmonization Working Party

AIMD

Active implantable medical device

AMDF

African Medical Device Forum

ANVISAAgência Nacional de Vigilância Sanitária or ANVISA is the regulator ofdevices for Brazil.

CAB

Conformity Assessment Body. They are the bodies that undertake
conformity assessment against requirements. For medical devices, they
can be government agencies, national standards bodies, or private or
publicly owned companies.

CE

Conformité Européenne

CEG

Consensus error grid. The consensus error grid (also known as
the Parkes error grid) was developed as a tool for evaluating theaccuracy of a blood glucose meter.

CE marking

CE marking is a mandatory administrative marking that indicatesconformity with health, safety, and environmental protection standards
for products sold within the European Economic Area (EEA). The CE
marking is also found on products sold outside the EEA that have been
manufactured to EEA standards.

CMDE

Center for Medical Device Evaluation, part of the Chinese regulatory
agency, the NMPACGMContinuous glucose monitoring systems, that measure glucose ininterstitial fluid via a device implanted under the skin. Different from
SMBGs, that measure blood glucose levels from (usually) a fingerstickcollection.

CLSI

Clinical and Laboratory Standards Institutehttps://clsi.org/

Devices

For this report, encompasses medical devices and IVD medical devices

EC

European Commission

EU

European Union

FDA

Food and Drug Administration of the United States of America

FDA OTC

This abbreviation is used in this document to describe the FDA guidance,“Self-Monitoring Blood Glucose Test Systems for Over-the-Counter Use”
of September 2020. It can be found at the following link:

Guidance

Regulatory Profile for Glucose Self-monitoring Tools 5https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/self-monitoring-blood-glucose-test-systems-over-counteruse
GHTF

Global Harmonization Task Force

HbA1c

Glycated haemoglobin

HIV

Human immunodeficiency virus

iCGM

Intermittently viewed Continuous Glucose Monitoring System

IDF

The International Diabetes Federation

IEC

International Electrotechnical Commission

IFCC

International Federation of Clinical Chemistry and Laboratory Medicine

IMDRF

International Medical Device Regulators ForumIMDRF ToCIMDRF Device Market Authorization Table of Contents

InterpolInternational Criminal Police Organization

ISO

International Organization for Standardization

IVD

In vitro diagnostic

IVDD

In Vitro Diagnostic Medical Device Directive 98/78/EC of the European
Union

IVDR

In Vitro Diagnostic Medical Device Regulation (EU) 2017/746 of theEuropean Union

LMIC

Low- and middle-income country

MARD

Mean absolute relative difference, currently the most common metricused to assess the performance of CGMs.

MAUDE

Medical Device Adverse Event Reports

MDSAP

Medical Device Single Audit Program

MDD

Medical Device Directive 93/42/EEC of the European Union

MDR

Medical Device Regulation (EU) 2017/745 of the European Union

NMPA

National Medical Product Administration of China

NRA

National Regulatory Authority

PAHO

Pan American Health Organization

QMS

Quality management system

rtCGM

Real-time Continuous Glucose Monitoring System

SI

Système Internationale

SKUP

Scandinavian evaluation of laboratory equipment for point of care testing.
The purpose of SKUP is to improve the quality of near patient testing in
Scandinavia by providing objective and supplier-independent information
Regulatory Profile for Glucose Self-monitoring Tools 6about analytical quality and user-friendliness of laboratory equipment.
This information is generated by organizing SKUP evaluations.
SMBG

A system for self-monitoring of blood glucose. For this report, it refers
to those systems where a person living with diabetes self-collects
capillary blood and measures it with a glucose monitor.

STED

GHTF Summary Technical Documentation for demonstrating
Conformity to the Essential Principles of Safety and Performance ofMedical Devices

TMDA

Tanzania Medicines & Medical Devices Authority

TPLC

Total Product Life Cycle is a database of events reported to the US FDA
for a particular product type. The TPLC database combines data fromvarious FDA databases (data sources) to present an integrated recordof pre-market and post-marketing activity for medical devices.

UDI

Unique Device IdentifierUS(A)United States (of America)

WHO

World Health Organization

Regulatory Profile for Glucose Self-monitoring Tools 7

1. INTRODUCTION
According to the International Diabetes Federation (IDF), 463 million people worldwide were livingwith diabetes in 2019, many from low-and middle-income countries (LMICs) where inequalities inaccess to quality healthcare persist. Diabetes is often undiagnosed or inadequately treated, withpeople unable to access the essential medicines and devices they need. Over the next 25 years,
diabetes prevalence is expected to increase in all countries, with the greatest increase expectedin middle-income countries (Figure 1). 1
Figure 1. Top 10 countries or territories for number of adults (20–79 years) with diabetes (IDF
Diabetes Atlas1)

In 1989, the 42nd World Health Assembly (WHA) recognised that diabetes mellitus is a chronic,
debilitating and costly condition, and that it represents a significant burden on the public healthservices of Member States. It also acknowledged that the problem is growing, especially indeveloping countries. The Assembly called on Member States to assess the national importance ofdiabetes and to implement population-based measures, appropriate to the local situation, to preventand control diabetes.
Controlling diabetes requires management of glucose levels in people living with diabetes.
Accurate measurement of glycaemic levels enables many people to self-manage to avoid the direconsequences of uncontrolled disease. One way that the Assembly’s call for action can be realised,
therefore, is through enabling greater access to accurate, affordable, quality diagnostic tools forthe self-management of diabetes.
Self-monitoring has become a vital part of the solution for many people living with type 1 diabetes
and for certain individuals living with type 2 diabetes. Along with self-monitoring blood glucose
test systems (SMBGs), which require fingerstick-collected capillary blood, alternatives to testing,such as continuous glucose monitoring systems (CGMs), are enabling the individual to better
achieve glycaemic targets with less inconvenience. The advent of insulin pensand pumps has also
provided empowering self-management. The technology landscape is evolving quickly, and now
CGMs can be linked with appropriate software and other hardware to automatically deliver
appropriate doses of insulin. Standalone software applications are also providing the person withdiabetes with improved self-management support. These technologies, when applied
appropriately, can improve the lives and health of people with diabetes; however, there remains
inequity as to who benefits from these technological innovations.

1IDF Diabetes Atlas. https://diabetesatlas.org/en/sections/demographic-and-geographic-outline.html (Accessed 01

March 2021)

Regulatory Profile for Glucose Self-monitoring Tools 8

An important aspect of access is the regulation of the technologies used for self-monitoring of
this condition. This document has been created to review the current regulatory practices in place
for market authorisations of glucose self-monitoring tools (SMBGs and CGMs) used by individuals.
It also reviews the assessment mechanisms employed at an international level to ensure access tosafe, effective and quality devices for the self-monitoring of diabetes in LMICs. The aim is to gain
an overall understanding of these mechanisms and identify opportunities for improvement.
The focus of the report is an evaluation of the regulatory assessment mechanisms employed by
European Union (EU) and the United States of America (US). These two jurisdictions represent
mature regulatory systems for such technologies, which in both are considered as medical devices
and in vitro diagnostic (IVD) medical devices. Approvals of these devices from the EU and US arerecognised in various manners to expedite market access in many jurisdictions, regardless of ajurisdiction’s economic status. Countries as diverse as Australia, Ghana, Malaysia, Switzerland andSouth Africa all use reliance mechanisms that include the recognition of Conformité Européenne
(CE) mark (EU approval) or Food and Drug Administration (FDA) authorisation.
Understanding the regulatory assessment processes provides a means to understand the level ofassurance that can be placed in the clinical safety and performance profile of a self-monitoring
device. To provide context, the framework for regulation of devices is reviewed. To provide
comparison, a high-level overview of the regulation of glucose self-monitoring devices in Tanzania
and China is provided, as examples of countries with regulatory bodies that have committed toregulatory harmonisation efforts.
The report aims to identify some of the challenges and opportunities that arise due to the current
state of regulation of these technologies. An emphasis is placed on identifying measures to help
secure equitable access to quality devices for people living with diabetes, regardless of the locationof their use. The scope of this report is limited to those devices that allow self-monitoring of
glucose levels, i.e., SMBGs and CGMs.

Regulatory Profile for Glucose Self-monitoring Tools 9

2. DEVICES FOR SELF-MONITORING OF DIABETES
2.1. Self-monitoring blood glucose systems - SMBGs
Self-monitoring blood glucose systems are the most broadly available tools for self-testing of
glucose levels. These systems typically use capillary whole blood collected from a fingertip or
alternative anatomical sites. The systems are generally composed of:•Blood glucose meter (henceforth referred to as the meter), for use on multiple occasions;•

Blood glucose meter strips (henceforth referred to as strips), used only once for testing ofa specimen. The strips are provided by the manufacturer of the meter.

•

Lancets, to aid collection of capillary blood for testing. Lancets are single-use.

According to the internationally agreed terminologies, the meter and strips are, for regulatory
purposes, considered IVD medical devices. Lancets are medical devices.
An international standard, International Organization for Standardization (ISO) 15197 2 exists toassist manufacturers of SMBGs in developing accurate devices. The US FDA provides specificguidance 3 which also guides manufacturers in the expectations of the US regulator. These
documents have been created to reduce the incidence of problems identified with a SMBG. The
design of any device for self-testing must take into account the abilities of a broad range of users
and the need for robust and safe design. The meters need to be simple to use and maintain, andthe user needs to ensure that: the strips are appropriate for the meter; the strips are stored asindicated; and the blood sample is applied to the strip as indicated. These are tasks that need tobe simplified or explained sufficiently so that a result is accurate and will truly reflect theglycaemic status of the individual.

2.2. Continuous glucose monitoring systems - CGMs
A continuous glucose monitoring system monitors glucose levels in more or less real time. In highincome countries, the market for continuous glucose monitoring systems is growing. Although theuptake of these devices has been limited in low-income settings, this is not the case in many
middle-income settings, where their use is gaining in popularity, especially as they become more
simple, robust, and affordable. 4 There is strong consensus that the use of CGMs reduces
hypoglycaemic risk and increases the amount of time a person with diabetes can stay in the target
glucose range. 5
CGMs are recommended for certain subsets of people with diabetes. 6 They are available in several
formats. The system uses a replaceable sensor, worn just under the skin, measuring glucose levels
in interstitial fluid continuously throughout the day and night. A display unit, receives the resultsfrom the sensor (via a transmitter), using Bluetooth. The results are interpreted, and information
relayed to the user. The sensor is usually for short term use and is usually replaced every seven to
fourteen days, however new versions may remain in place for several months. In addition, somemodels are designed to be used with automated insulin dosing systems.

2ISO 15197:2013 In vitro diagnostic test systems – requirements for blood-glucose monitoring for self-testing in managing

diabetes mellitus
3https://www.fda.gov/regulatory-information/search-fda-guidance-documents/self-monitoring-blood-glucose-test-

systems-over-counter-use
4
https://www.globenewswire.com/news-release/2020/11/12/2125254/0/en/Continuous-Glucose-MonitoringDevice-Market-size-to-surpass-USD-12-billion-by-2026.html (Accessed 02 March 2021)
5Bruttomesso et al. The use of real time continuous glucose monitoring or flash glucose monitoring in the managementof diabetes: A consensus view of Italian diabetes experts using the Delphi method. Nutrition Metabolism andCardiovascular Diseases 2019;29 (5):421–31
6Type 1 diabetes in adults: diagnosis and management NICE guideline. Published 26 August 2015.
www.nice.org.uk/guidance/ng17

Regulatory Profile for Glucose Self-monitoring Tools 10

CGMs uniformly track the glucose concentrations in the body’s interstitial fluid, providing nearreal-time glucose levels. The glucose detected by CGMs is that which has left the blood and has
moved into the tissues. As such, there is a lag time for CGM readings of approximately 5–15
minutes, compared with readings from capillary blood. Thus, CGM results do not always matchblood glucose readings.
There are two classes of CGM (Table 1):•

Real-time CGM (rtCGM) have a transmitter attached to the sensor to continuously send
glucose results to a display unit. The display unit can provide alerts when the glucose level
reaches certain limits or changes too quickly. Fingerstick testing is needed to calibrate
rtCGMs at least twice daily on many devices.

•

Intermittently Viewed CGM (iCGM) has no transmitter piece. Instead, the user manuallyscans the iCGM sensor with a handheld reader (display unit) to see current and stored
results. Some devices can have optional automated alarms for when glucose levels reachcertain limits. The latest versions do not need calibrating with fingerstick testing andcomparison with readings from a SMBG device. This is primarily due to innovations insoftware algorithms, although also in part to new sensor technology and improved
manufacturing techniques.

Table 1. The two types of CGM
CGMs that measure glucose levels continuously and send results
Real-time CGM

automatically to a display unit, providing the user with automated alarms andalerts at specific glucose levels and/or for changing glucose levels.

Intermittently
viewed CGM

CGMs that measure glucose levels continuously but only display glucose
values when swiped by a reader (display unit) or a smart phone that reveals
the glucose levels.

These technologies facilitate daily management decisions and reduce the need for fingerstick
testing. CGMs address many of the limitations inherent in SMBG, as they provide a means to moreeasily identify glucose patterns. Both rtCGM and iCGM facilitate monitoring of time spent in thetarget glucose range (“time in range”). The readings from certain CGM can be used to calculate
insulin doses, again reducing the need for fingerstick testing. Challenges for their use include cost,user alarm fatigue, skin irritations, the lag time, and that regardless of the brand, fingerstick
glucose testing is still required in certain circumstances. Furthermore, accuracy of the glucose
measurements is not constant, and varies depending on the blood glucose concentration and therate of blood glucose exchange.5
In high-income countries, the current trend towards more personal ownership of a patient’s
medical journey has become a driver for increased use of CGMs. Although the uptake of thesedevices has been limited in low-income settings, in many middle-income settings, they are gaining
in popularity, especially as they become simpler and more robust.
According to internationally agreed regulatory definitions, the sensor, the transmitter, the display
unit and associated software are medical devices. A specific standard exists to assist
manufacturers in defining performance metrics for CGMs (Clinical and Laboratory Standards
Institute [CLSI] POCT05). 7 This guideline covers how CGM data should be assessed for accuracy,
7Clinical and Laboratory Standards Institute. Performance Metrics for Continuous Interstitial Glucose Monitoring. 2nd
ed. POCT05. 2020

Regulatory Profile for Glucose Self-monitoring Tools 11

how CGMs should be assessed for factors that can decrease accuracy, and how CGMs should be
operated for optimal performance. In addition, the CEN/ISO/IEEE 11073 8 family of standards fordevice communication provides guidance that enables communication between medical, healthcare and wellness devices, and external computer systems. These standards also provide guidanceon automatic and detailed electronic data capture of client-related and vital signs information,and of device operational data.

8CEN ISO/IEEE 11073 Health informatics – Medical / health device communication standards

Regulatory Profile for Glucose Self-monitoring Tools 12

3. AN OVERVIEW OF THE REGULATION OF MEDICAL DEVICES
The purpose of this section is to provide an overview of how medical devices and diagnostic tests(known as IVDs) are regulated in certain jurisdictions.
To provide context and a better understanding of the regulations, this section describes important
regulatory harmonisation efforts that are undertaken, including the efforts by international
regulatory bodies and the World Health Organization (WHO) to ensure best regulatory practice isadopted globally. These efforts should help democratise access to quality self-monitoring tools
for diabetes.
International efforts towards harmonising regulation of medical devices were originally initiatedby a group comprised of regulators and industry from the US, Australia, Canada, the EU andJapan—jurisdictions with established and mature regulatory systems for medical devices in thel990’s. This group was called the Global Harmonization Taskforce (GHTF). The purpose of the
GHTF was to encourage the convergence in regulatory practices related to ensuring the safety,
effectiveness, performance and quality of medical devices, promoting technological innovationand facilitating international trade. The primary way in which this is accomplished was via the
publication and dissemination of harmonised guidance documents on basic regulatory practices,which can be adopted/implemented by member national regulatory authorities. GHTF recognised
the need to create agreed definitions, an important starting point in ensuring common regulatory
pathways. This group no longer exists but has been replaced by a regulators-only group, theInternational Medical Device Regulators Forum (IMDRF). The expanded membership encompasses
other jurisdictions, such as Brazil, China, Singapore, South Korea and Russia. Low-income
countries can attain observer status under the umbrella of the Pan American Health Organization(PAHO) and the Asian Harmonization Working Party (AHWP). 9 IMDRF has adopted the definitions
and many of the working documents created by GHTF. These have now become fundamental
starting points for many jurisdictions implementing regulation of both IVDs and medical devices.

3.1. Definitions of medical devices and IVDs
The tools used for monitoring diabetes are generally acknowledged to fall into two types of healthproduct categories: IVDs or medical devices. As the name proposes, IVDs are regarded in mostjurisdictions as a specific subset of medical devices. It is important to know the differences, tounderstand the approaches to their regulation.
The following definitions were created by GHTF and have been adopted in their entirety or withslight modifications in legislation in many countries. 10

3.1.1. Medical device‘Medical device’ means any instrument, apparatus, implement, machine, appliance, implant,
reagent for in vitro use, software, material or other similar or related article, intended by the
manufacturer to be used, alone or in combination, for human beings, for one or more of thespecific medical purpose(s) of:•diagnosis, prevention, monitoring, treatment or alleviation of disease;•diagnosis, monitoring, treatment, alleviation of or compensation for an injury;•

investigation, replacement, modification, or support of the anatomy or of a physiologicalprocess;•

supporting or sustaining life;•

control of conception;•

disinfection of medical devices;

9http://www.ahwp.info/
10GHTF/SG1/N071:2012 Definition of the Terms ‘Medical Device’ and ‘In Vitro Diagnostic (IVD) Medical Device’

Regulatory Profile for Glucose Self-monitoring Tools 13

•providing information by means of in vitro examination of specimens derived from thehuman bodyand•does not achieve its primary intended action by pharmacological, immunological or
metabolic means, in or on the human body, but which may be assisted in its intended
function by such means.

3.1.2. IVD medical device‘IVD medical device’ means a medical device, whether used alone or in combination, intended by
the manufacturer for the in vitro examination of specimens derived from the human body solely
or principally to provide information for diagnostic, monitoring or compatibility purposes.
IVD medical devices include reagents, calibrators, control materials, specimen receptacles,
software, and related instruments or apparatus or other articles and are used, for example, for thefollowing test purposes: diagnosis, aid to diagnosis, screening, monitoring, predisposition,
prognosis, prediction or determination of physiological status.
Of importance to note in these definitions are the following aspects:•

A medical device does not achieve its “primary intended action by pharmacological,
immunological or metabolic means”. Such means would render it a medicine.

•For regulatory purposes, an IVD is distinguished from other medical devices, primarily
because it is used with “specimens derived from the human body”. It is not applied to thebody, therefore according to GHTF definitions, a continuous glucose meter, which isplaced transcutaneously to measure glucose levels, is NOT an IVD but a medical device,even though it measures glucose from a bodily specimen (interstitial fluid). The purposeof this separation is to change the types of controls a manufacturer needs to ensure theproduct is safe to use, as an IVD is not invasive and cannot directly harm a patient, whereas
an invasive device can cause direct harm.

3.1.3. Devices
For the purposes of this report, the term “devices” will be used in a generic manner, to refer toboth medical devices and IVDs.

3.2. Internationally agreed regulatory framework
3.2.1. Evolution of regulation of medical devices and IVDs compared with medicines
Medicines have been regulated since the first half of the last century and most WHO Member
States have established agencies to regulate this class of essential health products. The regulationof medical devices and IVDs as separate entities only occurred much later, evolving frominnovation in the device sector as well as the differences in risk profiles seen with the diversity of
medical devices. Hence, the concept of quality systems for medical devices (in place of emphasis
on purely good manufacturing practice) arose not only in response to serious problems associatedwith the manufacturing of both medicines and medical devices, but also from the variety of
products, the fact devices have multiple components sourced from many different sites, amagnitude of principles of operations and various modes of action, and that the quality systems
approach provided a more principle-based means to accommodate this variety and improve
quality.
GHTF has proposed that regulation of devices should be risk-based, with regulatory controls (preand post-market), commensurate to the risk to the individual or to public health. Given that IVDs
will almost always pose an indirect risk to patients, GHTF proposed that they are as regulated asa subset of medical devices, and that special rules should apply, to account for this shift inregulatory risk profile.

Regulatory Profile for Glucose Self-monitoring Tools 14

Although this framework has been agreed at an international level, its implementation is notuniversal, with many established regulatory regimes bringing in harmonised requirements overtime.

3.2.2. The GHTF model for regulation of medical devices and IVDs 11
The fundamental life cycle of a medical device (and IVD) demonstrates that medical device
development is a continuous process with interdependencies at various stages of the development
cycle (Figure 2).
Figure 2. Medical device lifecycle

Regulatory controls can be placed at all or any of these phases of the lifecycle. GHTF proposed arisk-based model to regulation of devices, simplified by breaking the lifecycle into the three major
GHTF/AHWG-GRM/N1R13:2011 The GHTF Regulatory Model

11

Regulatory Profile for Glucose Self-monitoring Tools 15

regulatory phases: pre-market, placing on the market and post market. Figure 3 schematicallydescribes the different regulatory points of interaction.
Figure 3. Product life cycle: linear representation with applied processes

3.3. Critical elements of the GHTF regulatory model
The key subsystems of the GHTF regulatory model are:•risk-based pre-market controls, of which the requirement for technical documentation
forms a major control;•a system for post-marketing vigilance and surveillance;•

a quality management system (QMS) and risk management process encompassing thelifecycle; and•a regulatory audit process to periodically assess conformity throughout the lifecycle of thedevice.

These elements are interrelated and mutually interdependent. Fundamental to this model is theunderstanding that the level of regulatory control will be decided based on risk to the patient or
public health, which is determined by the stated intended use and classified according to a set ofrisk classification rules. Constants within the model are: the requirements that determine quality(an effective QMS), safety and performance (technical documentation to demonstrate thefulfilment of the essential principles of safety and performance through appropriate design, andverification and validation activities). How these latter aspects are executed is dependent on therisk profile of the device, the intended use, and its novelty.
Important concepts in the regulation of devices are as follows:

3.3.1. Conformity Assessment
The manufacturer has to establish the compliance of their product and of their QMS when placing
a new product on the market. Conformity assessment is undertaken by the regulator orconformity assessment body (CAB) for most products as a pre-market activity, to enable market
authorisation. The manufacturer must review the compliance of their product and QMS
constantly throughout the device lifecycle. This provides the means to demonstrate that the
product remains in conformity with essential requirements over its lifecycle.

Regulatory Profile for Glucose Self-monitoring Tools 16

Device regulations should specify the manner in which the manufacturer demonstrates to theregulatory authority that its medical devices comply with the legislation. The necessary
conformity assessment elements are:•technical documentation;•

establishment of safety and performance (if needed through clinical trial / performance
evaluation);•a QMS;•a system for post-marketing surveillance;•

a declaration of conformity;•

the registration of manufacturers and their medical devices by the regulatory authority.

3.3.2. Risk classification
The risk profile of a device, according to the GHTF model, will determine the level of regulatory
control placed on a device, such as if a device requires pre-market assessment by a CAB. It isdetermined by a series of principle-based rules. The lower the risk a device poses for the patient,
the user or others, the less controls are needed to ensure safety and performance. Lessons havebeen learnt from the adoption in Europe of classification based on a list of named devices or
diseases, albeit that these were listed because they have a higher risk. With the arrival of newly
discovered pathogens and new technologies, the weakness of such lists was quickly evident. GHTF
realised that classifying a device based on a set of principles, including the risk level, provides formore regulatory flexibility based on science.
A different set of rules is used to classify IVDs to those used for other medical devices. Regardlessof which set of rules is used (according to the type of device), by applying the risk classification
rules to the intended use of a device, the rules will determine which of four risk classes a device
will be categorised as. Class A are devices deemed to be the lowest risk class, and Class D thehighest. Pre-market controls for Class A are generally minimal, although a manufacturer must
declare, and therefore is legally obliged, to follow the regulatory conditions to assure safety,
quality and performance. Conversely, a Class D device will be subjected to the most stringent preand post-marketing controls. With the GHTF model, conformity assessment is usually required
for all classes except Class A, to achieve approval for placing on the market. The level of evidence
required to be submitted for assessment increases with the risk class.

3.3.3. Technical documentation
A manufacturer is obliged under the GHTF model to prepare and hold technical documentationthat shows how each medical device was developed, designed and manufactured together withthe descriptions and explanations necessary to understand the manufacturer’s determination withrespect to such conformity with a regulation. This technical documentation is updated asnecessary to reflect the current status, specification and configuration of the device. Dependingon the regulatory system, the full technical documentation or summaries or excerpts of these
documents are submitted to the regulator as part of conformity assessment. GHTF proposed aharmonised set of documents to be submitted for regulatory review. This is known as the GHTF
Summary Technical Documentation for demonstrating Conformity to the Essential Principles of
Safety and Performance of Medical Devices, 12 or STED. The extent of evidence in a STED is likely toincrease with the class of the device, its complexity, and the extent to which it incorporates newtechnology. WHO prequalification and a number of jurisdictions have adopted the STED as theformat for submitting the documentation for review.

12http://www.imdrf.org/docs/ghtf/archived/sg1/technical-docs/ghtf-sg1-n063-2011-summary-technical-

documentation-ivd-safety-conformity-110317.pdf andhttp://www.imdrf.org/docs/ghtf/archived/sg1/technical-docs/ghtf-sg1-n011r17-conformity-to-safety-principlesmedical-devices-021025.pdf

Regulatory Profile for Glucose Self-monitoring Tools 17

However, IMDRF has now replaced the STED with the IMDRF Device Market Authorization Tableof Contents (IMDRF ToC). 13 Although designed primarily to assist in enabling electronic
submissions of technical documentation, it also provides more transparency around therequirements for technical documentation. The IMDRF ToC is used in conjunction with aclassification matrix that describes the level of detail to be submitted for each requirement (if any)dependent on the risk class. At time of publication, Health Canada and the Chinese NMPA haveadopted the IMDRF ToC as the mandatory format for device applications.

3.3.4. Use of standards
This GHTF generic model for regulation of such a diversity of devices adapts to productspecificities by reference to use of standards. International consensus standards are based upon
science, technology and experience and generally reflect the best experience of industry,
researchers, consumers, regulators and other experts worldwide. 14 As such, these standards canbe a means of demonstrating internationally acknowledged best practice or state of the art. Where
international consensus standards are used, harmonisation efforts are enhanced. These standards
provide a benchmark for both manufacturers and regulators to assess product quality andperformance.
For IVDs, the use of standards extends from consensus papers or written standards to include
material standards. WHO provides international biological reference preparations which serve as
reference sources of defined biological activity expressed in an internationally agreed unit (the“Système Internationale [SI] Unit”). Use of these material standards, where they exist and areapplicable, offer a manufacturer a means of demonstrating that a product meets quality andperformance standards and provides a harmonised system for comparison.

3.3.5. Unique Device Identifier (UDI)
A powerful tool for post-marketing surveillance, the unique device identifier or UDI, was proposedby the GHTF, and continues to be a pivotal subject supported by IMDRF. When adopted by ajurisdiction, the “label of most devices will include a UDI in human—and machine—readable form,
which will ultimately improve patient safety, modernise device post-marketing surveillance, andfacilitate medical device innovation”. 15 According to IMDRF, the UDI system is intended to provide
a single, globally harmonised system for positive identification of medical devices. 16
In the most basic format, the UDI would be a coded number registered with standards
organisations, and would incorporate a variety of information, including (but not limited to) the
manufacturer of the device, expiry dates, the make and model of the device, and any special
attributes that the device may possess.
The UDI is composed of two parts: Device Identifier (UDI-DI) + Production Identifier (UDI-PI) =Unique Device Identifier (UDI). UDI-DI + UDI-PI = UDI.
•

Unique Device Identifier - Device Identifier (UDI-DI): The Device Identifier of the UDI isa unique numeric or alphanumeric code specific to a model of medical device and that is
also used as the "access key" to information stored in a UDI database. This mandatory,
fixed portion of a UDI identifies a manufacturer’s specific product and package
configuration.

•

Unique Device Identifier - Production Identifier (UDI-PI): The Production Identifier of
the UDI is a numeric or alphanumeric code that identifies the unit of device production

13 http://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-190321-nivd-dma-toc-n9.pdf andhttp://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-190321-ivd-mdma-toc-n13.pdf
14 IMDRF/Standards WG/N51 FINAL 2018 Optimizing Standards for Regulatory Use
15
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/unique-deviceidentification-system-udi-system (Accessed 10 February 2021)
16UDI Guidance. Unique Device Identification (UDI) of Medical Devices IMDRF/UDI WG/N7FINAL:2013

Regulatory Profile for Glucose Self-monitoring Tools 18

when one or more of the following is included on the package label of the device. The
different types of Production Identifier(s) may include:a) The Lot or Batch within which a device was manufactured;b) The Serial Number of a specific device;c) The Expiration Date of a specific device;d) The date of manufacture (may not be required if other Production Identifiers areon the label);e) the Version
Figure 4: Composition of a UDI label 17

The requirement for a label to include a UDI has now been implemented in a number ofjurisdictions, notably the US, China, South Korea. The EU is transitioning to inclusion of a UDI onlabelling as part of its role out of the new regulations for medical devices and IVDs.
The following figure provides a very high-level perspective of the linkages that are achieved fromthe application of a UDI. 18 Across those systems, the different aspects of the UDI (UDI-Dis, UDIPIs and data from UDI databases) are used to link device identification data across separated
systems and to use the results of that linkage to improve the quality of healthcare delivery or
healthcare research or market surveillance.

17

Adapted from https://easymedicaldevice.com/udi/ (Accessed 15 April 2021)

18 System requirements related to use of UDI in healthcare including selected use cases

IMDRF/UDI WG/N54 FINAL:2019 (Accessed 15 April 2021)
Regulatory Profile for Glucose Self-monitoring Tools 19

Figure 5: Linkages via the UDI

3.4. Global adoption of the GHTF regulatory model
The GHTF model has been designed so that it can be adopted in a progressive manner, allowing
jurisdictions with no prior experience in the regulation of devices to incrementally and logicallyadopt aspects of regulatory activity as expertise and capacity is increased. Meanwhile, theadoption of the GHTF model, principles and guidance in a jurisdiction’s regulatory practice canprovide the possibility for reliance on the work of other jurisdictions. For a WHO Member State,
this is perhaps one of the greatest strengths of the work of harmonisation. For a manufacturer, italso means fewer unique regulatory requirements to meet, keeping down costs associated withregulatory compliance.
It is important to note that this initiative for regulatory harmonisation of medical devices is nolonger only undertaken by IMDRF. There are several other similar initiatives, including the AHWP
and the African Medical Device Forum (AMDF). All, however, are building on the formative work of
GHTF. As such, this initial work of GHTF will act as the benchmark or reference point for thisreport.

3.5. Implementation of medical devices and IVD regulation
Effective regulatory systems are seen as the basic building block of a well-functioning healthsystem. According to WHO, 19 many countries still lack effective regulatory systems for any type of
health product. Among its 194 Member States, only 50 countries (26%) have what are consideredmature regulatory agencies, whilst the remaining countries have suboptimal regulatory systems.
Just over half are at the lowest level of maturity. A recent report warned that “when manufacturersof medical products want to bring their products to market, they face a landscape of disparate
regulations, unclear regulatory pathways, frequent delays in accessing essential medicines andlimited transparency. This suppresses innovation, drives up medicine prices and opens the door
for substandard and falsified medical products. It also leaves regulators ill-prepared to deal withpublic health emergencies, where, for example, a vaccine or medicine may need to be fast-tracked
through the regulation process”. 20
19https://www.who.int/medicines/technical_briefing/tbs/TBS2019_WHO_RSS_Capacity_Building_GBT.pdf
20https://doi.org/10.3389/fmed.2020.00457 (Accessed 21 March 2021)

Regulatory Profile for Glucose Self-monitoring Tools 20

In 2015/2016, WHO conducted a desktop survey to determine the status of a legal framework for
medical devices in Member States.5 Unlike the previous report, this survey did not include ananalysis of the effectiveness of implementation. However, the numbers indicated that regulatory
systems for devices are in many cases non-existent or, if present, unlikely to be effective (Figure6). Of the 194 participating Member States, 113 responded positively to having a legal framework
for medical devices in place, and 53 indicated no legal framework. In total, 121 Member States
claimed to have a national regulatory authority responsible for implementing and enforcing
medical device regulations.
Figure 6. Number of countries with established basic regulatory elements based on the 113
countries that have a legal framework for medical devices, analysed by World Bank Income
group 21Further analysis by WHO (personal communication) indicated that of the approximate 60% of
Member States with medical device regulation, only approximately 50% of these included theregulation of IVDs. Thus, for many jurisdictions there is no or very limited regulatory oversight oftechnologies for self-monitoring of diabetes.
Prior to this survey, in 2014, Member States of the United Nations voted at the 67th WHA in favourof the following mandate:
WHA Resolution 60.29: “to encourage Member States to draw up national or regional guidelines forgood manufacturing and regulatory practices, to establish surveillance systems and other measures
to ensure the quality, safety and efficacy of medical devices and, where appropriate, to participate ininternational harmonisation”.
As with medicines, harmonisation of technical requirements for device regulation is a desirable
goal for many reasons:•Companies have to generate only one data set for all regions thereby reducing the cost ofdevelopment of regulatory documentation; this can lead to lower prices•

Common regulatory standards for scientific evaluation and inspection facilitate regulatorycommunication and information sharing•

Local products are more likely to be acceptable for export to other countries•

Faster access to devices of high public health value•

Increased competitiveness resulting from newly developed common markets 22

21Regulation of medical devices. https://www.who.int/medical_devices/safety/3_2.pdf?ua=1
22 https://www.who.int/medicines/areas/quality_safety/regulation_legislation/harmonization/en/

Regulatory Profile for Glucose Self-monitoring Tools 21

There have been considerable efforts by WHO, its donors and other bodies to implement or
improve the number of regulations for devices as a result of this resolution, coupled with thefindings of the WHO survey. However, progress is slow, and funding for such activities has notbeen as consistent as it is for strengthening regulation for medicines.
Probably most successful has been the effort made by the AHWP. Using the fundamental
regulatory principles defined by GHTF, AHWP has supported the implementation of regulation of
medical devices, including of IVDs, in a number of Asian jurisdictions.
Yet despite efforts by IMDRF, AHWP and WHO (see next section) to strongly support the
introduction of harmonised regulation, some of the jurisdictions recently implementing device
regulation have introduced regulations that vary from the recommendations for a harmonised
framework. These potentially can block good products getting to market due to the complexitythat the additional requirements introduce.

3.6. WHO model regulatory framework for medical devices including IVDs 23
Realising that many countries were struggling with the adoption of effective regulation of devices,
WHO produced a guidance on developing a regulatory framework. This guidance builds on thework of GHTF, IMDRF and AHWP. It recommends a two- or a three-step approach and is now
being used as the basis for implementation. An emphasis is placed on leveraging the work oftrusted regulatory assessments through regulatory decision-making recognition and reliance. A
number of African Member States are using this model to introduce regulation and a new initiative,
the Africa Medical Devices Forum (AMDF), has arisen to support it. AMDF is supported both by
WHO and the Africa Union.

3.7. Global progress in implementing medical device regulation
In summary, a significant number of LMIC WHO Member States lack effective regulation of
medical devices and IVDs, with the African region having the most significant gaps. Although
efforts are ongoing, progress is sporadic and not all efforts have resulted in a system based on theprinciple of harmonisation that enables recognition and reliance, which are essential concepts ofeffective regulation. 24
The lack of (1) adoption and (2) uniformity, results in difficulties in access in many WHO Member
States. It also results in a lack of desire by manufacturers to place their devices on the market insome jurisdictions. Often, medical devices and especially IVDs are low value, low-income
commodities. The effort required to navigate the regulatory pathway in some LMICs can welloutweigh potential financial rewards for many manufacturers. This is usually due to unclear andshifting requirements. A recent report authored by several WHO employees also warned that thelack of a robust regulatory system leaves a jurisdiction vulnerable to substandard and falsified
medical products. 25
In high-income WHO Member States, the influence of IMDRF is apparent. New regulations areoften modelled on IMDRF guidance. The benefits are clear. As many of these jurisdictions importa large proportion of their devices, the ability to use reliance mechanisms means limited
regulatory agency resources can be placed into post-marketing monitoring rather than premarket conformity assessment.

http://www.who.int/medical_devices/publications/global_model_regulatory_framework_meddev/en/

23

24https://www.who.int/medicines/areas/quality_safety/quality_assurance/GoodRegulatory_PracticesPublicConsult.

pdf
25https://doi.org/10.3389/fmed.2020.00457 (Accessed 21 March 2021)

Regulatory Profile for Glucose Self-monitoring Tools 22

3.8. Roles and responsibilities within a regulatory system: manufacturers, national
regulatory authorities (NRAs) and Conformity Assessment Bodies (CABs)
GHTF identified the basic roles and responsibilities of the various actors within a regulatory
system. Tables 2–4 illustrate some of the most important aspects. National regulatory authorities(NRAs) have legal authority to oversee the enactment of the medical device legislation. They areoften responsible for ensuring that products released for public use are evaluated appropriately
and meet national standards of quality and safety. The NRA may engage certain conformity
assessment bodies (CABs) to undertake some of the assessment activities on their behalf (forinstance, QMS certification, or in the case of Europe, all pre-market assessment activities) or they
may undertake the conformity assessment activity themselves. A CAB is the legal entity that
performs a conformity assessment against regulations and relevant standards, the output of which
is a conformity assessment report which carries a judgement of conformity or non-conformity. A
CAB may be a certification body for a QMS, an inspection body, a certification body for a productor process, a testing laboratory or a validation/verification body.
Table 2. NRA roles and responsibilitiesa
GeneralPre-market

Post-market

QMS

QMS audit

Clinical safety• Linkgovernment
policies andpriorities toregulatory
systemb• Define ‘medical
device’• Establish
adverse event
reportrequirements• Establish QMS
requirement• Establish audit
requirements,
includingfrequency• Enforce humansubject
protections andethicalframework• Consultstakeholdersb• Draft and adopt
laws andregulationsb• Appoint andoversee CABs
• Maintainadequateresources• Enforce laws
and regulations• Import/export
controls• Registration of
manufacturers
importers, anddistributors anddevice listing• Establish
medical deviceclassification
rules• Establish‘essential
principles’ of
safety andperformance• Recognisestandards• Pre-market
conformity
assessment• Establish andmaintainnational
vigilance
database• Evaluate
adverse event
reportsreceived• Monitor
manufacturer
investigationand field safety
corrective
actions• Recognise ISO
13485 standard• Oversee CAB
audits• Conduct audits• Establish andoversee ethics
committees• Oversee clinicalinvestigations• Enforce laws
and regulations• Evaluate
adverse event
reports• Handle
information
concerning
adverse event
reports• Exchange
information
with otherauthorities

Not exhaustive. Requirements and roles vary depending on class of devices.
activities may be the responsibility of the Ministry of Health, depending whether the NRA is an independent
executive agency or fully part of the Ministry of Health.

abTheseRegulatory Profile for Glucose Self-monitoring Tools 23

Table 3. Roles and responsibilities of a CABa
GeneralPre-market

Post-market

QMS

QMS audit

Clinical safety• Comply with
CAB
designation
criteria (ofNRA)• Verify
manufacturer
determinationof device classb• Assessmanufacturer
post-marketingsurveillanceand vigilance
reportingsystems during
QMS auditsb

N/A• Conduct andreportmanufacturer
QMS auditsb• Audit/assess
manufacturer’s
clinicalevaluation
processb• Maintainaccreditation, if
required• Maintainappropriatequalifiedresources• Conformity
assessment(review
summarytechnical
documentation,
includinglabelling)b• Verify
standards
appropriately
applied bymanufacturerb• Assessmanufacturer
corrective
actions fromaudit findings• Assessmanufacturer
field safety
corrective
action systems
during QMS
auditsb• Assess clinicalevaluation andclinicalevidence duringconformity
assessmentb

aSome or all of the roles of the CAB may be performed by the NRA.

The level of assessment is related to the risk class of the device.

b

Table 4. Roles and responsibilities of a manufacturer
GeneralPre-market

Post-market

QMS

QMS audit

Clinical safety• Comply withnational
requirements• Determine
whether
product is‘medical
device’• Establish andmaintain postmarketingsurveillancesystem (part ofQMS)• Establish andmaintainappropriate
and effective
QMS, including
risk
management(e.g., ISO13485,
ISO14971)• Subject of
periodic audits• Conductclinicalevaluation(ongoing)• Investigate andevaluatecomplaints andproduct
experience
information• Register, list
• Determine
appropriate
essential
principles• Applyappropriate
standards• Prepare, holdand maintaintechnical file
(QMS)

• Prepare andsubmitvigilance
reports• Respond toaudit findings• As needed
conduct,monitor, reportclinicalinvestigations(per ISO14155/20916)• As appropriate,
conduct fieldsafetycorrective
actions• Submit STED• Prepare andholddeclaration ofconformity

Regulatory Profile for Glucose Self-monitoring Tools 24

4. REGULATION OF SELF-MONITORING DEVICES
FOR DIABETES
Self-monitoring enables people living with diabetes to achieve appropriate metabolic control,
avoiding hypoglycaemia and reducing the likelihood of developing long term complications ofhyperglycaemia, such as blindness or renal failure. CGMs further facilitate diabetes care in such a
way as to maximise user care whilst minimising discomfort. However, the proper functioning ofthese devices is absolutely essential for people with diabetes; malfunctions can have serious
consequences and, in some cases, could result in death. 26 In addition to the impact of incorrect
dosage due to malfunctions, there are harms associated with an implanted device. As such,
regulatory requirements and associated conformity assessment mechanisms should be risk-based
and fit for purpose.
This section will review regulatory frameworks for SMBGs and CGMs in the US, the EU, theRepublic of Tanzania and the People’s Republic of China. Both, the EU and the US, have been
regulating devices for several decades and thus have evolved systems. Because of this, many
jurisdictions use reliance mechanisms and accept CE marking and FDA market authorisation inplace of undertaking comprehensive pre-market assessment. Thus, the assessment of theframeworks for these two jurisdictions in this report will be detailed. In addition, both the EU andUS represent jurisdictions where considerable manufacturing occurs.
To provide contrast, a high-level overview of the regulation of self-monitoring devices in China
and Tanzania will be examined, to demonstrate how the WHO and GHTF models are being adopted
in a recent member of IMDRF and in a lower middle-income country that almost exclusively
imports all devices.

4.1. The regulation of devices in the USA and the EU
4.1.1. Comparison of US and EU regulation
By comparing the regulatory scrutiny mechanisms for self-monitoring devices, this section
endeavours to understand the impact of those mechanisms on device safety and performance.
Comprehensive details of the US and EU regulations with respect to devices for self-monitoringof glucose levels can be found in Appendices 1 and 2.
4.1.1.1. Important similarities in approach
It is important to understand that some fundamental regulatory requirements for devices within
US and EU law are basically aligned, with requirements for manufacturing under an appropriate
QMS aligned to ISO 13485, which incorporates risk management, essential requirements for safety
and performance, use of standards, design specification and design control, validation andverification of design, clinical evidence, a summary of safety and performance, the need forsuitable labelling, registration and or listing for market access, and a system for post-marketingsurveillance. The details differ in certain particular sub-requirements (for instance, which
standards are recognised, reporting requirements, labelling including use of a UDI), and in how
they are assessed for conformity.
4.1.1.2. Important differences in approach
Although the EU and the US have been regulating devices for several decades, the origins of device
regulation in each jurisdiction have arisen due to specific challenges, resulting in somefundamental differences in the approach to how each jurisdiction regulates devices. For example:•

For the US, device regulation relies on a strictly centralised process through the FDA, thus
has the advantages of centralisation and common rules. This contrasts with the EU, which

26Adapted from “Medical Devices in Diabetes Care: A statement on behalf of the European Association for the Study ofDiabetes” 2013

Regulatory Profile for Glucose Self-monitoring Tools 25

regulates medical devices utilising not only each Member State’s regulators, known ascompetent authorities, but also with a network of decentralised, private CABs known as
notified bodies. Notified bodies are responsible for the pre-market assessment of devices
in Europe. The competent authorities of each EU Member State are responsible for clinical
trial authorisation, market vigilance and for oversight of the notified bodies. The EU
approach is intended in part to provide greater choice and faster time to market for device
manufacturers needing pre-market conformity assessment. There is much debate
regarding the benefits and weaknesses of these two approaches. The FDA provides aconsistent and rigorous approach, whereas the strength of the EU approach with respect
to use of notified bodies lies in its agility and efficiency of pre-market regulatory
evaluation. The jury is still out as to which is better for patients. 27,28.
•

For the FDA regulations, where market authorisation is via the so called 510(k) pathway(see Appendix), the authorisations are valid without any time limits. The EU requires
renewal of the QMS certificate and of the product certificate in regular intervals of three
to five years.

•

New regulations (IVD regulation [IVDR] and medical device regulation [MDR]) currently
under transition in the EU are bringing many changes. Some of the significant items that
may have an impact on assuring quality devices for diabetes are as follows:–

The use of a UDI. This is already an FDA requirement but is being phased in for the
IVDR and the MDR.

–

IVD clinical evidence under the IVDR must include evidence of the clinicalassociation of the marker being detected and the clinical conditions as claimed.
This is known in the IVDR as scientific validity and is not an FDA requirement.
However, the relationship of glucose with diabetes is well established and as such,
does not represent any new risk for current devices on the market.

•

For implanted medical devices, there will be a requirement under the MDR that each
implant has an implant card. This will apply to CGMs and is not a requirement under thecurrent EU Directive, nor for the FDA. These cards will (i) enable the patient to identify the
implanted devices and to get access to other information related to the implanted device(e.g., via the medical device database EUDAMED, and other websites); (ii) enable patients
to identify themselves as persons requiring special care in relevant situations e.g., security
checks; (iii) enable, for instance, emergency clinical staff or first responder to be informed
about special care/needs for relevant patients in case of emergency situations.

•

Both the EU IVDR and MDR have increased requirements for post-marketing activities andreporting. These activities are in addition to those for FDA and for the EU Directives.

•

Finally, all certificates issued by a notified body, informing of conformity with the newRegulations, must be included in the new medical device database EUDAMED. The public
will be able to identify devices with CE marking due to these certificates. Suchtransparency of market authorisation already exists for the FDA, but has not existed with
the EU Directives.

4.1.2. Comparison of the US and EU regulation of self-monitoring blood glucose
devices (SMBGs)
For the FDA, SMBGs are classified as Class II devices (moderate risk) and are regulated by the510(k) notification, which requires product developers to present data demonstrating that thedevice functions similarly to a previously approved device. Under the outgoing IVD Directive of
the EU, where a list-based classification system was in place, SMBGs qualified as part of list B of
Annex II of the IVD Directive. This list represents moderate risk, requiring notified bodyconformity assessment. Under the forthcoming EU IVD Regulation, SMBGs will be Class C, the27 “Regulation of Medical Devices in the United States and European Union” Kramer D, Shuai X and Kesselheim M. N Engl
J Med 2012; 366:848-855
28 Drugs and DevicesComparison of European and U.S. Approval Processes Van Norman, G. JACC: Basic to Tranlsational
Science 2016; Vol 1 No399–412

Regulatory Profile for Glucose Self-monitoring Tools 26

second highest risk category, also requiring notified body conformity assessment. Table 5 provides
a high-level overview of the similarities and differences in regulatory scrutiny of SMBGs.

Regulatory Profile for Glucose Self-monitoring Tools 27

Table 5. Comparison of conformity assessment activities by the CAB for SMBGs
General alignment in assessment criteria
Potential source of difference in assessment criteria
Significant difference in assessment criteria
CAB procedures

US FDA

EU CE IVDD
(outgoing IVD
Directive)

EU CE IVDR
(new IVD
Regulation)

Potential impact of the difference on safety and performance

Classification

Focus of assessment

Class II, 510 (k)Annex II List B

Class C

Pre-market
assessment required

Y

Y

Y

QMS required

Y

Y

Y

CAB assessment
team

FDA technical unit
at Center for
Devices andRadiological Health

Notified bodies IVD
directive

Notified bodies
IVDR

Comprehensive CAB
assessment activities(Note:+ indicates mandatory
assessment action,+/- indicates anoptional activity attime of productassessment)

Technical + clinical+/quality

Technical+/quality

Technical + clinical •+/- quality•

FDA and IVD Directive requirements similar. IVDR requirements enhanced

FDA approach more consistent (one CAB)•

FDA inspection of QMS may not coincide with technical file assessment, butlater. FDA inspects all Class II manufacturers on a 2-year cycle.
The EU IVDD requires a technical documentation review of each product, but the
QMS aspects related to that product may not be reviewed until later if the
manufacturer has already been inspected under the IVDD.
For the EU IVDR, a manufacturer can submit several similar self-tests, and only
one will receive an in-depth technical assessment at point of application. The
remaining technical documentation files will be assessed over the life of thecertificate. As with the IVDD, the QMS may be audited simultaneously, or later
if the system has already been audited.

Regulatory Profile for Glucose Self-monitoring Tools 28

Recognition ofstandards forconformity
assessment?

Y
FDA consensus
standards

Y
EN harmonized
standards

Y
EN harmonized
standards;
none harmonised
at time of
publication

Official recognition of
ISO 15197:2013

N

Y

Assumption thiswill be harmonised

Regional specificguidance for
performance of
SMBGs

Y

N

N

The difference in the performance standards is addressed in Section 7, Analysis
of effectiveness of current assessment tools (part 1)

Technical documentation content for assessment
Risk management
report and risk
benefit ratio
discussion submitted

Y

Y

Y

Scientificvalidity/clinicalassociation

N

N

Y

Analytical
performance studies

Y

Y

Y

Clinical performancestudies (using device
in question)

Y

N

Y

Specific requirements
for lay user studies

Y

Y

Y

Testing population
requirements forclinical performancestudies

Equivalent to US
population

Equivalent to a
EuropeanPopulation

Equivalent to a
EuropeanPopulation

Likely to have little impact as the association of glucose measurements withdiabetes is well established

The IVDR will rectify some of the problems associated with the IVD Directive’s
lack of specific requirements in this area

Unlikely to have a high level of impact, if any

Regulatory Profile for Glucose Self-monitoring Tools 29

Clinical evaluation
reportY

YY

Software/firmware
assessment including
cybersecurity

Y

Y

Y

Electrical safety

Y

Y

Y

Post-marketing
performance plan andreportNN

Y (updated yearly) ••Post-marketingsurveillance plan andreportNN

Y (updated yearly)

Adverse event
reportingY

Y

Y

Notification ofsignificant changes

Y

Y

Y

Mandatory QMS
audit by CAB required
before application?

N

Y

Y

Surveillance audit of
QMS by CAB

YEvery 2 years

Y (every 1–2 years)

Y (yearly)

Mandatory
unannounced audits
of QMS by CAB

NN

Y (once per 5
years)

Subject matter expert
review of lot releaseprocedures during
review of STEDY

N

Not mandatory

QMS auditor review
of lot releaseprocedures

optional

optional

optional

May be required by FDA in individual circumstances.
IVDR requirements ensure performance is monitored
IVDR requirements ensure safety and performance are monitored

QMS audit
FDA prioritises inspections by risk (e.g., new manufacturer) and gives higher risk
devices/situations a higher priority, including Class II devices. An ISO 13485
certificate is sufficient for application.

This obligation is considered a strength of the FDA review process.

QMS audit will look at a selection of technical documents associated with thedevice.

Regulatory Profile for Glucose Self-monitoring Tools 30

Other requirements
Independent
performance
evaluation a prerequisite

N

N

N

UDI requirementsYN

Y (in transition)

UDI provides traceability in supply chain.
Potential to improve adverse event reporting and discourage counterfeiting

Public databases toinform of market
authorization,
adverse eventsYN

Y (in transition)

Greater transparency for end users where this is implemented

4.1.3. Comparison of the US and EU regulation of Continuous Glucose Monitoring systems (CGMs)
For the FDA, most CGMs have recently been down-classified to Class II devices (moderate risk) and are thus regulated by the 510(k) notification, which
requires product developers to present data demonstrating that the device functions similarly to a previously approved device. For the EU, theclassification is similar. For those that are not associated with delivery of insulin, they are Class IIb, the second highest classification for medical devices,making them moderate to high risk. Table 6 provides a high-level overview of the similarities and differences in regulatory scrutiny of CGMs.

Regulatory Profile for Glucose Self-monitoring Tools 31

Table 6. Comparison of conformity assessment activities by the CAB for CGMs
General alignment in assessment criteria
Potential source of difference in assessment criteria
Significant difference in assessment criteria
CAB Procedures

US FDA

EU CE MDD
(outgoing
medical device
directive)

EU CE MDR
(new medical
deviceregulation)

Potential impact of the difference on safety and performance

Classification

Class II, 510 (k)Class IIb

Class IIb/III

For the EU, the class can alter depending on specific attributes.

Pre-market
Assessment required

Y

Y

Y

QMS required

Y

Y

Y

CAB assessment team

FDA technical unit
at Center for
Devices andRadiological
HealthNotified bodies
MDD

Notified bodies
MDR

Comprehensive CAB
assessment activities(Note:+ indicates mandatory
assessment action,+/- indicates anoptional activity attime of productassessment)

Technical +clinical +/- quality

Quality +/technical +clinical on arisk- based
approach

Quality +/technical +clinical on arisk- based
approach

FDA and MDD requirements similar. MDR requirements enhanced.
FDA approach more consistent (one CAB)••

FDA inspection may not coincide with technical file assessment.
FDA inspects all Class II manufacturers on a 2-year cycle.
For both the EUMDD and MDR, the assessment of the technicaldocumentation of at least one representative device is obligatory
for CE marking (of an application of a number of similar devices ismade to the NB), with review of remaining similar devices to occur
over the certification cycle, unless the device is Class III. If Class
III, the technical documentation must be reviewed.

Regulatory Profile for Glucose Self-monitoring Tools 32

Recognition ofstandards forconformity
assessment?

Y
FDA consensus
standards

Y
EN harmonised
standards

Y
EN harmonised
standards;
none
harmonised attime ofpublication

Recognition of CLSI
POCT05 performance
metrics

Y [x]

N

N

The difference in the performance standards is addressed in Section 7.
Analysis of effectiveness of current assessment tools (part 1)

Special controls

Y

N

N

May have potential to impact safety and performance

Technical documentation for assessment
Risk management
report and risk benefit
ratio discussion

Y

Y

Y

Biocompatibility
studiesY

YY

Analytical
performance studies

Y

Y

Y

Clinical performancestudies (using device
in question)

Y

Y

Y

Specific requirements
for lay user studies

Y

Y

Y

Clinical evaluation
reportY

YY

Software/firmware
Assessment

Y

Y

Y

Sterility

YYY

Regulatory Profile for Glucose Self-monitoring Tools 33

Electromagnetic
Compatibility

Y

Y

Y

Electrical safety

Y

Y

Y

Environmental testing

Y

Y

Y

Interoperability

Y

Y

Y

Calibration

Y

N

Y

Environmental testing

Y

Y

Y

Sensor life andstabilityY

YY

Human factors

Y

Y

Y

Cybersecurity

Y

N

Y

The MDR will rectify some of the problems associated with the MDD’s lackof mandatory requirements in this area

Post-marketingclinical performanceplan and reportN

Plan onlyY

May be required by FDA in individual circumstances.

Post-marketingsurveillance plan andreportNN

Y (updated
yearly)Adverse event
reportingY

Y

Y

Notification ofsignificant changes

Y

Y

Y

Mandatory QMS audit
by CAB required
before application?

N

Y

Y

Surveillance audit of
QMS by CAB

YEvery 2 years

Y(every 1–2
years)Y(yearly)

The MDR will rectify some of the problems associated with the MDD’s lackof mandatory requirements in this area

QMS audit
FDA prioritises inspections by risk (e.g., new manufacturer) and gives higher
risk devices/situations a higher priority, including Class II devices.

Regulatory Profile for Glucose Self-monitoring Tools 34

Mandatory
unannounced audits
by CAB

N

N

Y(once per 5
years)

Testing population
requirements forclinical performancestudies

Equivalent to US
population

Equivalent to a
Europeanpopulation

Equivalent to a
Europeanpopulation

Unlikely to have a high level of impact, if any.

UDI requirementsYN

Y (in transition)

UDI provides traceability in supply chain.
Potential to improve adverse event reporting and discourage counterfeiting

Implant card

N

N

Y

Potential to improve patient safety following field safety correction actions

Public databases toinform of market
authorization, adverse
eventsY

N

Y

Greater transparency for end users where this is implemented

Other requirements

Regulatory Profile for Glucose Self-monitoring Tools 35

4.1.4. Comparison of the regulatory mechanisms
Tables 5 and 6 demonstrate that the regulation of self-monitoring devices is not uniform. Thisvariability may impact on the quality, safety and accuracy of these devices.
4.1.4.1. Analysis of the FDA oversight
New FDA guidance for SMBGs, “Self-Monitoring Blood Glucose Test Systems for Over-theCounter Use”, released in September 2020, requires that a manufacturer submit their procedures
for lot release. These must be approved by the FDA. A lot release procedure describes how the
manufacturer will assure that each new batch (or lot) of product will deliver the same performanceof the lot before. This requirement represents best practice for these products.
The US FDA has recently down-classified most CGMs to that of Class II, the same as for SMBGs.
The FDA has made the change due to approximately 20 years of experience with these products
and considered that they do not have a Class III risk profile. A Class II device in the US is subject
to a 510(k) pre-market clearance. The evidence provided for a 510(k) submission for performancerelies on establishing substantial equivalence with a preceding device that is already on themarket. Typically, this is done in a laboratory setting and human testing is rarely required. The
principle of substantial equivalence therefore also runs the risk of compounding bias (creating
greater inaccuracy) if the comparator device has a systematic bias in reporting.
However, even for a 510 (k), the FDA provides greater transparency in its requirements for selfmonitoring devices than do the EU Directives or Regulations. It lists for each type of device (SMBG
or CGM), the consensus standards that may be utilised; in the case of CGMs, special controls; andin addition, provides many FDA guidance documents that clarify requirements. Such transparency
not only assists the manufacturer in understanding the requirements, but also ensures that theassessors from the agency are consistent in how they assess. The staff undertaking theseassessments for the FDA all rest in one centre (CDRH) providing the opportunity for a standardised
assessment procedure. In addition, the fact that the requirements are clearly enunciated, meansthat suboptimal studies by a manufacturer are more likely to be identified than in the case of theEU, where under the Directives there were many different notified bodies, thus greater variety inthe staff undertaking the assessment and resultant variability in assessment standards, as well as
less clarity in requirements.
Finally, the FDA now requires all devices to include a UDI. This identifier will greatly assist ininvestigations of problems associated with the device.
4.1.4.2. Analysis of the EU oversightOf significance, under the new EU Regulations, the requirements for quality systems and theirinspection are strengthened, as are the requirements for documentation of processes andprocedures for the manufacturer. Manufacturers must have a plan and reports for post-market
clinical performance follow-up that includes reactive and proactive measures. These will bechallenging to develop for these devices for self-testing. The manufacturer must update theirclinical evaluation report on a yearly basis with the information from the clinical performance
follow-up, as well as other post-marketing measures. These new requirements will be investigatedduring the QMS audit. Also, during the five-year cycle of a QMS certificate, the notified body is
expected to undertake one unannounced audit. These have the potential to identify poor quality
practices.
For SMBGs, a major change under the new Regulations with potential to impact on performanceis the enhanced emphasis on clinical performance. Under the EU IVD Directive, the emphasis wason analytical performance data. This no longer suffices.
Perhaps one of the biggest weaknesses of the Directives that is being rectified with theintroduction of the new regulations is the extremely strict requirement by the European
Regulatory Profile for Glucose Self-monitoring Tools 36

authorities that, with the new requirements, the notified body assessment staff are highly qualified
to undertake the assessments. This should indeed raise the bar for quality clinical evidence.
A weakness of the EU system compared to that of the FDA is the relative lack of good guidance
documents. For SMBGs, EN ISO 15197 is noted as a harmonised standard, and obviously applies tothese devices, but few other harmonised standards are as explicitly applicable to these devices.
The FDA recognises the CLSI standard series, and these are acknowledged as state of the art for
many aspects of IVD validation and verification. Unfortunately, the CLSI standards are notrecognised in the EU. This, however, does not prevent a manufacturer from using them. With time,
more standards will be available for IVDs in the EU.
Although the EU IVD Regulation is in many ways a superior tool for regulation than the IVD
Directive, when it comes to SMBGs, there is one weakness. A manufacturer may apply for a groupof SMBGs to be assessed by a notified body. The notified body is only obliged to comprehensively
assess, in the first instance, one of these products. It must have a plan to review remaining
technical files within the certificate lifecycle. The documentation chosen at time of application
should be that representing the highest risk. The notified body must justify its choice.
A strength of the Regulations compared to the Directives is that a summary of safety andperformance for each self-monitoring device must be made available on the medical device
database, Eudamed. This summary, akin to that of the FDA summary of safety and effectiveness,
will also be publicly available. It is hoped that this will provide greater transparency to theassessment process to which the application was subjected.
As is in the US, under the new Regulations, all devices will eventually be required to have a UDI on
the label, the benefits of which have already been described. For CGMs, it is also required under
the new EU regulation that everyone with a sensor has an implant card. Implant cards are intended
for patients to be able to identify information about devices that is published elsewhere, forexample in Eudamed. It is also intended for the patient to identify themselves in case of field safety
corrective action or other issue. It is hoped that such initiatives will improve knowledge of any
ongoing safety issues associated with these devices.

4.2. High level overview of regulation of self-monitoring devices by
China and Tanzania
4.2.1. China
China has one of the highest numbers of adults with diabetes in the world. This statistic is unlikely
to change in the next decade. The national regulator of medical devices and IVDs in China is the
NMPA. China has become a member of the IMDRF and its processes are aligning more with time.
Since becoming a member, China has fully adopted 14 IMDRF guidelines and partially implemented
another 14. 29 In 2020, China was revising its prime medical device legislation. The outputs of thisactivity were not available at the time of publication, but it is certain that there will be changes.
This bodes well for more harmonised international requirements.
The approval process for imported goods in China depends on the class of the medical device. The
class is determined by the “product panel”, which in turn groups devices with similar applications
and product codes together. For low risk, Class I devices the NMPA will make a direct decision formarket approval, but a technical review is required for Class II and III medical devices. SMBG strips
are Class II. The CAB for imported products is the Center for Medical Device Evaluation (CMDE),
part of the NMPA. Type testing by an NMPA-certified tester or testing laboratory is often
necessary. Approval is valid for five years. It should be noted that requirements differ for local
production, which is regulated on a provincial basis. These requirements are not the subject of
this review.

29http://www.imdrf.org/docs/imdrf/final/meetings/imdrf-meet-200921-singapore-webconference-05.pdf

Regulatory Profile for Glucose Self-monitoring Tools 37

4.2.1.1. Product classification
According to Provisions for In-vitro Diagnostic Reagent Registration (Decree No.5 of China’s Foodand Drug Administration), SMBGs will be Class II IVDs. Similar guidance identifies CGMs as ClassII devices.
Locally manufactured Class II medical devices and IVDs are reviewed by the food and drug
regulatory department of the provinces, autonomous regions and municipalities directly under
the central government. Class III domestic medical devices and IVDs are reviewed by NMPA, andimported class II and class III medical devices are reviewed by NMPA. For all of the above, themedical device registration certificate is issued after approval. 30 Hence the standards ofassessment may differ for Class II devices because locally produced Class II devices are assessedby provincial regulators, whereas imported Class II devices are subject to assessment by theNMPA.
4.2.1.2. Clinical trials for SMBGs
Pre-market approvals for Class II and Class III medical devices and IVDs in China will, by default,
require clinical trials in support of the application, unless the applicant can:•Identify its product on the clinical trial exemption list;•

Provide sufficient information about a predicate device that is NMPA-approved; or•Provide sufficient overseas clinical trial data.

These requirements are largely the same whether a company is a domestic or foreign applicant.
4.2.1.3. Standards
China insists on national standards. These are often identical, or at least similar, tointernational standards. A significant outlier, however, is that the NMPA does not accept
International Electrotechnical Commission (IEC) 60601-X test report forms for the testingof electromagnetic compatibility and electrical safety. IEC 60601 is a series of technicalstandards for the safety and essential performance of medical electrical equipment. The NMPA
insists on a device complying to national specifications for electrical safety.
4.2.1.4. QMS requirements
Although China has its own QMS requirements, there is high alignment with ISO 13485. Therefore,
an ISO 13485 certificate can be used to support a market application. The NMPA may request
review of the audit report associated with an ISO 13485 certificate to ensure China-specificrequirements have also been met.
4.2.1.5. UDIChina has issued rules on the adoption of the UDI (2019, No 66). This initiative is being piloted withhigh-risk implants, such as brain and heart implants. Its final rollout will greatly assist in postmarketing investigations.
4.2.1.6. Clinical evaluation
A clinical evaluation is mandatory for imported Class II and III medical devices (SMBGs and CGMs
are class II). This evaluation is based on the results of clinical investigations/studies (e.g.,
published in specialist literature) and on non-clinical data. A comparator device can be used forthis. Clinical investigations are required if no equivalent devices can be found, and safety and

30NMPA Provisions for In-vitro Diagnostic Reagent Registration. Updated 2019-07-25; Provisions for Medical Device

Registration. Updated 2019-07-25

Regulatory Profile for Glucose Self-monitoring Tools 38

efficacy cannot be proven with other clinical and non-clinical data. The NMPA has published its
own guidelines (“Medical device clinical evaluation technical guidance”). This is similar
to MEDDEV 2.7/1, but has different priorities.
The requirements for clinical investigation are still different, but recent changes are making China
an increasingly attractive option for clinical trials for IVDs and medical devices.
4.2.2. Tanzania
The regulator of IVDs in Tanzania is the Tanzania Medicines and Medical Devices Authority(TMDA). Tanzania has been one of the first African nations to adopt the WHO regulatory model
framework, undertaking a stepwise approach to build up its capacity to regulate devices. As such,
Tanzania has been chosen to highlight a jurisdiction maximising the benefits of harmonised
regulation.
All medical devices, including IVDs, must have marketing authorisation by TMDA unless given
special approval by the TMDA. A list of all registered medical devices and IVDs is available on the
TMDA website. The agency has implemented regulations that, in general, adopt the GHTF
definitions that consider the class based on the GHTF classification scheme, which determines
which products require registration (classes B to D are evaluated for quality, safety andperformance; notification is required for class A devices). Guidance documents exist to assist in
the process of registration and notification. A registration is valid for five years.
4.2.2.1. Classification
According to the TMDA website, SMBGs are Class C IVDs and CGM devices may be either class B
or C. No definitions have been provided to define duration of use. If the use of a CGM is consideredlong term usage, it will be Class C, if not it will be a Class B. The guidance provides no clear
difference in the expectations of the regulator between submissions for a class B and a class C
device.
Thus, SMBGs and CGM devices must be registered with the TMDA. This requires submission of a
STED and QMS documents, for evaluation of acceptability. The TMDA website states the following:“In the course of evaluation of applications, reference will routinely be made to ISO standards andother internationally accepted guidelines to include those published by WHO and IMDRF to ensurethat IVDs of good quality, safe and performing are authorised for marketing. An abridged assessment
procedure will be adopted for IVDs which have been prequalified by WHO to avoid duplications andhasten registration of such products.”
Similar wording regarding assessment standards is also provided for medical devices.
Internal procedures allow for a comprehensive abridged assessment of a device with provenmarket authorisation in the US, Canada, EU, Australia or Japan (personal communications withstaff at the TMDA, 27 January 2021). This demonstrates that Tanzania is implementing reliancemechanisms and can do so due to the harmonisation of their legal framework with international
best practice. SMBGs and CGMs in Tanzania are primarily on the market via the route of thisregulatory reliance mechanism.
4.2.2.2. QMS
Evidence to demonstrate an effective QMS that will be accepted by the TMDA includes a CE
certificate issued by a notified body designated in Europe. ISO 13485 certificates issued by notified
bodies designated in Europe for the purposes of the IVD directive will also be accepted.

4.2.2.3. UDIAt this point of time there is no indication that Tanzania will require labelling including a UDI.

Regulatory Profile for Glucose Self-monitoring Tools 39

4.2.2.4. Post-marketing requirements
The TMDA website states:“Applicants should also note that they will now be required to conduct post marketing surveillanceof IVDDs in countries that mimic Tanzania conditions to accrue information on their quality, safety
and performance to testify whether they still meet registration requirements post approval. Suchinformation should be prepared and submitted after every two years (biennial) as indicated inthese guidelines and pursuant to the Tanzania Medicines and Medical Devices (Control of Medical
Devices) Regulations, 2015.”
As such, there are mechanisms in place whereby the regulator can ensure ongoing compliancewith the Tanzanian regulations.

4.3. WHO Prequalification
Although WHO is not a regulatory body, it undertakes assessments of safety and performance of
certain health products, e.g., medicines and devices for malaria, to inform procurement and tosupport its programmes. In 2019, WHO announced that the WHO Prequalification (PQ) of IVDs
programme will prequalify SMBGs. The timing of this activity was planned for 2020, but PQ has
experienced significant time shifts in implementation forced by the COVID-19 pandemic. It is
unknown when it will be implemented.

4.3.1. The PQ Procedure
In its current incarnation, WHO PQ for IVDs is modelled on the GHTF model for high risk IVDs, inthat the assessment includes a comprehensive evaluation of a product, with the following steps
being undertaken. The WHO Prequalification procedure consists of the following assessment
steps:• Technical documentation assessment. The product dossier, submitted according tointernationally recognised practices, is reviewed with the purpose of gaining an
understanding of the product, its safety and performance, design and manufacture; anddetermining if the manufacturer’s QMS is of an adequate standard to warrant aninspection.
• QMS assessment. The manufacturing site inspection is carried out to assess compliancewith the quality management standard ISO 13485, with focus on the suitability of theimplemented processes and procedures for the reliable supply of products in LMICs.
• Performance evaluation. Laboratory evaluation of the product using specimens, often
sourced globally, to verify performance and to assess the operational and characteristicsof the product. WHO has approved certain laboratories to undertake this activity, using
a WHO approved protocol.
• Instructions for Use Review. If a product has been deemed to meet minimum standards ofquality, safety and performance via the three steps noted above, WHO will review the
instructions for use to ensure that the contents are appropriate for the end users(including their usability) and any claims are supported by the evidence.
When a product is successfully prequalified by WHO, it will be added to the list of WHO
Prequalified products and be eligible for procurement with United Nations funding. The Global
Fund also acknowledges the PQ status as a means of being eligible for purchase with Global Fund
donations.
The programme has evolved with time and now includes evaluation of important post-market
responsibilities of the manufacturer, including for instance, reporting of adverse events and ofsignificant changes. Countries with weak or non-existent regulatory systems in place put highemphasis in the findings of WHO PQ, at times, preferring this reliance mechanism than others
offered by recognition of decisions made by a single regulatory authority.

Regulatory Profile for Glucose Self-monitoring Tools 40

4.3.2. Abridge PQ procedure
Some products undergoing PQ will already have had comprehensive conformity assessment by amature regulatory agency as part of market authorisation. WHO leverages this assessment andfocuses its efforts on aspects that may be of less relevance to a high-income countries. For
instance, the importance of performance of a test using specimens sourced from Africa and othersuch jurisdictions will be investigated by PQ, as will the ability of the manufacturer to support
users in these countries.

Regulatory Profile for Glucose Self-monitoring Tools 41

5. CHALLENGES ASSOCIATED WITH THE USE OFSMBGS AND CGMS
5.1. Access to accurate devices
SMBGs are the most affordable option for self-management for many people living with diabetes.
The tests are simple but require collection of fingerstick blood using an uncomfortable procedure.
To ensure good performance, the design of any device for self-testing must consider the abilities
of a broad range of users and the need for robust and safe design. The meters need to be simple
to use and maintain, and the user needs to ensure that the strips are appropriate for the meter,
the strips must be stored as indicated, and the blood sample applied to the strip as indicated.
These are tasks that need to be simplified or explained sufficiently so that a result is accurate andwill truly reflect the glycaemic status of the individual.
The availability of the international standard, ISO 15179 (current version 2013) “IVD test systems –requirements for blood-glucose monitoring systems for self-testing in managing diabetes
mellitus” has led to improved accuracy with these devices, as the standard specifies design
verification procedures and requires the validation of performance by the intended users. With
this standard, and the requirement in a number of jurisdictions for pre-market assessment by theregulator for conformance with this standard, there has been a general trend to better, moreaccurate SMBG devices on the market in high-income countries.
Despite this, there are still SMBGs with variable performance. Lack of effective regulation in many
LMICs means that there is a real potential in some settings for access to unregulated, poor-quality
SMBGs, made more affordable as they bypass stringent regulatory assessment processes.
Anecdotal evidence (personal communication) informs that some manufacturers offload batchesof test strips that do not meet accuracy criteria for stringent regulators to less regulated markets.
Furthermore, reports from the International Criminal Police Organization (Interpol) indicate all
jurisdictions are vulnerable to receipt of counterfeit and substandard devices, thus this issue is a
global concern.
It has been almost two decades since the first CGM was marketed, and in that time accuracy, as
measured by the mean absolute relative difference (MARD) reading between the CGM and alaboratory-based state of the art blood glucose system, has fallen from around 25% to 9–11% withthe latest generation (factory calibrated) systems. 31 This equates to a large improvement inaccuracy. The relative inaccuracies between the two measurements (CGM versus laboratorybased blood glucose result) are in part due to the difficulty in accurately measuring glucose levels
in interstitial fluids compared to the relative ease in a measuring a blood sample (volume of
specimen, variable glucose lag time), as well as the inherent inaccuracies in the comparator assay
itself. Device inaccuracy is still not optimal and can lead to harm to the user. Unlike SMBGs, there
is no internationally accepted standard guiding the design of verification procedures or assay
validation for CGM performance comparable with the ISO 15197 standard. Although SMBGs can bedirectly compared with laboratory methods to analyse differences and accuracy in measuring
glucose levels, no consensus has been developed for comparing CGM devices to reference
methods. This is because there is no reference measurement procedure for glucose in interstitial
fluid.

5.2. Adverse events reported for the use of self-monitoring devices
5.2.1. Adverse event reporting
Major regulators have requirements for adverse event reporting associated with the use of theirdevice contributing to death or serious injury. Manufacturers may also report when they becomeaware that their device has malfunctioned and would be likely to cause or contribute to a death
31Forlenza et al. Factory-calibrated continuous glucose monitoring: how and why it works, and the dangers of reuse
beyond approved duration of wear. Diabetes Technology & Therapeutics 2019;21(4):222–229

Regulatory Profile for Glucose Self-monitoring Tools 42

or serious injury if the malfunction were to recur. Such malfunctions or device deficiencies may
include any inadequacy in the identity, quality, durability, reliability, safety or performance of adevice, user errors or inadequacy in information supplied with the device.
It is important to note that device deficiencies of IVDs are often hard to monitor, and even more
so when the IVD is used for self-testing. This is due to the indirect nature of harm with an IVD,
whereby it is not the device itself, rather it is the impact of a false result, that directly causes harm.
If a SMBG is not accurate, and there is no warning indicating this, it may only be when a serious
adverse event occurs as a result of the failure, that the problem is recognised.
The FDA maintains a publicly accessible database (Total Product Life Cycle [TPLC] database) ofadverse events covering both pre-marketing and post-marketing data concerning medical
devices. It includes information about device classification product codes, pre-market approvals,
pre-market notifications (510[K]), Medical Device Adverse Event Reports (MAUDE), and Center for
Devices and Radiological Health medical device recalls.
The following information was obtained from the FDA TPLC database, using the product codes
NBW (code for SMBG) and QBJ (code for CGM). A review of TPLC for SMBGs identified thefollowing issues:
5.2.1.1. FDA Adverse event reporting for SMBG
From a total of 167,778 events reported since 2016, Tables 7 and 8 describe the top 10 adverse
events for SMBGs and their consequences reported to the FDA. Of note, although device
deficiencies did not result in patient harm in a large proportion of these events (142,954 or 86.3%
claimed), 5,828 users (3.7%) did report a significant finding (either hyper- or hypoglycaemia).
Table 7. Top 10 device deficiencies reported to the FDA associated with SMBGs (11 March 2021)
Device problem

Number of
eventsPercentage of totalreported events

Failure to power up

38,751

23.1

Device displays incorrect message

38,691

23.1

Incorrect, inadequate or imprecise result or readings

13,7388.2

Incorrect or inadequate test results

13,486

8.0

Loss of power

7,609

4.5

High test results

7,140

4.3

Device operates differently than expected

5,074

3.0

Device alarm system

3,436

2.0

Gauges/meters

2,663

1.6

Low test results

2,161

1.3

Table 8. Top 10 clinical outcomes reported to the FDA associated with SMBG adverse events (11March 2021)
Clinical problem

Number of events

Percentage of totalreported events

No known impact or consequence to patient

79,76047.7

No consequences or impact to patient

63,19437.8

Hyperglycaemia

3,084

1.8

Hypoglycaemia

2,744

1.6

Shaking/tremors

2,354

1.4

Sweating

2,081

1.2

Dizziness

1,986

1.2

Regulatory Profile for Glucose Self-monitoring Tools 43

Clinical problem

Number of events

Percentage of totalreported events

No clinical signs, symptoms or conditions

1,276

0.8

Loss of consciousness

799

0.5

Weakness

777

0.5

5.2.1.2. FDA adverse event reporting for CGMs
From a total of 351,058 clinical problems reported since 2018, Tables 9 and 10 describe the top 10
adverse events for CGMs and their consequences reported to the FDA. Of note, although device
deficiencies did not result in patient harm in a large proportion of these events (346,327 or 98.7%
claimed), 1,496 users (0.4%) did report a significant finding (being hyper- or hypoglycaemia, lossof consciousness or diabetic ketoacidosis, the latter of which there were 119 reports).
Table 9. Top 10 device deficiencies reported to the FDA associated with CGMs (11 March 2021)
Device problem

Number of events

Percentage of totalreported events

Wireless communication problem

126,308

34.4

No device output

97,790

26.6

Imprecision

56,546

15.4

Premature end-of-life indicator

19,566

5.3

Device displays incorrect message

18,547

5.0

Communication or transmission problem

11,211

3.1

Appropriate term/code not available

7,786

2.1

Detachment of device or device component

4,578

1.2

Unintended application program shut down

3,847

1.0

Retraction problem

3,729

1.0

Table 10. Top 10 clinical outcomes reported to the FDA associated with CGM adverse events (11March 2021)
Clinical problem

Number of events

Percentage of totalreported events

No consequences or impact to patient

244,264

66.5

No known impact or consequence to patient

6,812518.5

No clinical signs, symptoms or conditions

5,6723

15.4

Hypoglycaemia

899

0.2

Reaction

538

0.1

Loss of consciousness

283

0.1

Erythema275

0.1

Hyperglycaemia

255

0.1

Foreign body in patient

242

0.1

Itching sensation

223

0.1

5.2.1.3. Observations from the findings
It is not possible to draw strong conclusions from the results of these searches. Databases such asthese are limited when it comes to providing information about the severity of the adverse events.
The search results have limited use for determining the incidence of an adverse event (that is, howoften the adverse event has occurred in users of a particular medical device), or the likelihood ofRegulatory Profile for Glucose Self-monitoring Tools 44

a user experiencing that adverse event. This is because the search results do not include criticalinformation such as the total number of users of a medical device, the number of medical devices
supplied in the country of reporting, or the incidence of adverse events prior to the reporting
timeline. Additionally, caution must be made when using the search results to make accurate
numerical comparisons between adverse events associated with different medical devices. As
such, the following observations are only indicative of where problems with these devices may lie.
Approximately 23% of reported SMBG deficiencies were related to inaccurate results. This finding
was obtained by including the following categories of complaints:•

Incorrect, inadequate or imprecise result or readings•

Incorrect or inadequate test results•

High test results•

Low test results•

Missing test results•

False reading from device non-compliance

Meanwhile, 15.6% of device errors for CGMs were identified as being related to inaccuracy. The
only relevant category reported associated with inaccuracy was for imprecision. Similarly,
problems associated with usability were assessed. For SMBGs, approximately 4.5% of reported
deficiencies were due to either the device operating differently than expected, a device
operational issue or lack of sufficient information. Only about 0.1% of reported CGM problems
were directly attributed to usability issues.

5.2.2. Agência Nacional de Vigilância Sanitária (ANVISA) actions
Although other jurisdictions have databases for adverse event reporting, no others provide thecomprehensive data set available on the FDA website. Anecdotal evidence provided via theBrazilian regulator, ANVISA (personal communication, January 2021), revealed that many problems
are reported for use of sensors with CGM. The main issue apparently is around clarity of
instructions. The need for instructions to be adapted for the intended use population is vital. This
must all be done under the control of the manufacturer’s quality system, even if third parties are
involved to assist. In addition, in 2018, “RESOLUTION-RE NO. 3,161, OF NOVEMBER 16, 2018”
published on the official Brazilian government website, 32 resulted in the cancellation of 17
registrations of various SMBG and CGM devices. The reason for this cancellation was lack ofevidence of conformity with ISO 15197:2013. A number of the products were CE marked and had
FDA authorisation. ANVISA had requested the data from manufacturers, however, it had not been
forthcoming.

5.3. Substandard and counterfeit devices
In 2020, Interpol reported that in March that year, more than 37,000 unauthorised and counterfeit
medical devices were seized, the vast majority of which were surgical masks and self-testing kits(for human immunodeficiency virus [HIV] or glucose), but also various surgical instruments. 33
Rapid test formats are simple to make, if quality is not a consideration, and HIV and glucose selftests are the most prone to criminal misconduct. With both tests, the impact of an invalid or afalse result is serious. As such, the need for unique identifier systems such as the UDI is clear. Also,
there is a need for affordable controls so that users can routinely check new batches for efficacy.
Regardless of the stringency of regulatory oversight, criminal activity will endure; however, it ishoped that the prevalence is significantly curbed with current regulatory measures to ensure
greater traceability and transparency.

https://www.in.gov.br/web/guest/materia/-/asset_publisher/Kujrw0TZC2Mb/content/id/50727633/do1a-201811-19-resolucao-re-n-3-161-de-16-de-novembro-de-2018-50727413 (Accessed 09 February 2021)
33Global operation sees a rise in fake medical products related to COVID-19. https://www.interpol.int/en/News-andEvents/News/2020/Global-operation-sees-a-rise-in-fake-medical-products-related-to-COVID-19 (Accessed 08
February 2021)
32

Regulatory Profile for Glucose Self-monitoring Tools 45

6. ANALYSIS OF THE EFFECTIVENESS OF CURRENTGUIDANCE FOR DEVICE DEVELOPMENT AND ASSESSMENT
Use of consensus driven standards and guidance provides both manufacturers and regulators withbenchmarks for acceptable design and performance features. The implementation of the various
iterations of ISO standard ISO 15197, IVD test systems: requirements for blood-glucose monitoring
systems for self-testing in managing diabetes mellitus, has resulted in improved performance. The
following section will review and compare the various guidance documents currently available andconsider their strengths and weaknesses as tools the development for accurate self-monitoring
devices. Intentionally highly technical in nature, it is hoped that this analysis will be useful for
regulators and will highlight areas for improvement in future revisions.

6.1. Self-monitoring blood glucose devices- SMBGs
This section analyses the differences that may contribute to variability in performance between
ISO 15197 and the FDA guidance document Self-Monitoring Blood Glucose Test Systems for Overthe-Counter Use: Guidance for Industry and Food and Drug Administration Staff, published in
September 2020.
The standard ISO 15197 was established in 2003, revised in 2013 and the current version was
harmonised with EU regulations in 2015. 34 Since its publication in 2003, many manufacturers of
SMBGs have used the standard to design their device and validation studies.
In 2016, the FDA released their own guidance document, Self-Monitoring Blood Glucose Test
Systems for Over-the-Counter Use, hence forth referred to as FDA OTC guidance, defining
requirements for SMBGs, stating that they believe “that the criteria set forth in the ISO 15197
standard are not sufficient to adequately protect lay-users using SMBGs because, for example, thestandard does not adequately address the performance of over-the-counter blood glucose test
systems in the hypoglycaemic range (…) or across test strip lots.” This guidance was updated in
September 2020. 35
A comparison of the current version of ISO 15197 and the FDA OTC guidance reveals that bothmainly address the same topics (Table 11). Both refer to, for example, robustness regarding
environmental and usage variation, the information provided by the manufacturer and analytical
performance. The most obvious differences between the two documents relate to the scope andapplicable acceptance criteria of the accuracy studies.

34International Organization for Standardization. In vitro diagnostic test systems - Requirements for blood-glucose
monitoring systems for self-testing in managing diabetes mellitus. ISO 15197:2013 2013.
35Food and Drug Administration. Self-Monitoring Blood Glucose Test Systems for Over-the-Counter Use - Guidance forIndustry and Food and Drug Administration Staff2020 11-Mar-2021. Available from:http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM380327.p
df

Regulatory Profile for Glucose Self-monitoring Tools 46

Table 11. Differences between ISO 15197 and FDA OTC guidance
ISO 15197
Evaluation

FDA

System accuracy

User performance
evaluation

Method comparison/user
evaluation

Measurements are
performed by trained
study personnel

Subjects naïve to therespective SMBG

At least 10% of the subjects
shall be naïve to selfmonitoring of blood glucose≥100 different subjects≥100 different subjects
from the intended use
population≥350 subjects from theintended use population

Defined distribution of
glucose concentrations
need to be tested

No defined distribution of
glucose concentrationneed to be tested

No defined distribution of
glucose concentration need to
be tested

Each sample is measured
twice with each of three
reagent system lots (600values, 300 per lot)

Single measurements fromone reagent system lot

Single measurements fromthree strip lots

Altered blood samples
allowed to coverextremes of themeasuring range

No need to cover complete
measuring range

Altered samples proposed tocover extremes of themeasuring range
50 altered blood samples at
low and high concentrations,
respectively

Acceptancecriteria

Lots

Comparison
samples

Glucose concentrations≥100 mg/dl(5.55 mmol/l): 95% of
measurements shall fallwith ±15% of thereference value

The same as ISO

Glucose concentrations<100 mg/dl(5.55 mmol/l): allowed
difference of ±15 mg/dl(0.83 mmol/l)

Glucose concentrations<100 mg/dl (5.55 mmol/l):
maximum deviation of ±15%

All glucose
concentrations: 99% ofvalues within zones A and
B of the CEG

All glucose concentrations:minimum of 99% values within±20%

Each of three reagent lots
separately has to fulfil
acceptance criteria

Evaluation of one reagent
lot

Evaluation of three reagent
lots, but results of one lot withinsufficient performance may
be compensated by two lotswith better performance

Perform duplicate
measure for eachcomparison sample

Perform duplicate measurefor the comparison sample

Duplicate measures are
optional

Take comparison
samples before and after
sampling for SMBG
testing

Only one comparison
sample is taken

Only one comparison sample
is taken

Regulatory Profile for Glucose Self-monitoring Tools 47

ISO 15197 stipulates two types of accuracy evaluations:••

System accuracy evaluation: Measurements with the SMBG are performed by trained
study personnel. In total, samples of 100 different subjects, 36,37,38,39 having a defined
distribution of glucose concentrations are included. For very low and very high glucose
concentration ranges, altered blood samples may be used: Up to all samples ≤50 mg/dl(2.77 mmol/l) or >400 mg/dl (22.2 mmol/l) as well as some of the samples ≤80 mg/dl(4.44 mmol/l) or >300 mg/dl (16.65 mmol/l). Each sample is measured twice with each of
three reagent system lots, resulting in 600 measured values (300 for each reagent systemlot). Subject samples must be distributed according to specification, which is helpful whenaccuracy evaluations of different systems are compared.
User performance evaluation: 100 different subjects, naïve to the respective SMBG, shallbe recruited from the intended use population 40,41,42,43. Measurements are performed by
the subjects with one reagent system lot.

Both studies may be combined with the same 100 subjects, provided that the user performancepart is performed first to ensure that subjects are still naïve to the SMBG.
The FDA guidance also requires a combined method comparison/user evaluation, i.e.,an evaluation with single measurements being performed by 350 subjects from the intended use
population using three test strip lots. 44 At least 10% of the subjects shall be naïve to self-monitoringof blood glucose (e. g., non-diabetic subjects).
The user samples may not sufficiently cover extremely low or high glucose concentrations.
Therefore 50 altered blood samples with glucose concentrations <80 mg/dl (4.44 mmol/l) and 50
altered blood samples >250 mg/dl (13.9 mmol/l) have to be added to the analysis.
It is unclear whether the same subjects may participate both in the user evaluation and provide an
additional sample for altering, therefore up to 450 measurements are needed for these accuracy
evaluations.
Both ISO 15197 and the FDA guidance for over-the-counter systems require a minimum numberof unaltered samples below 80 mg/dl (4.44 mmol/l) and above 300 / 250 mg/dl (16.7 /13.9 mmol/l), but the number of altered samples differs.
36Freckmann G, Link M, Schmid C, Pleus S, Baumstark A, Haug C. System Accuracy Evaluation of Different Blood Glucose

Monitoring Systems Following ISO 15197:2013 by Using Two Different Comparison Methods. Diabetes Technol Ther.
2015;17(9):635-48. doi: 10.1089/dia.2015.0085
37Pleus S, Baumstark A, Jendrike N, Mende J, Link M, Zschornack E, et al. System accuracy evaluation of 18 CE-marked
current-generation blood glucose monitoring systems based on EN ISO 15197:2015. BMJ open diabetes research & care.
2020;8(1). Epub 2020/01/21. doi: 10.1136/bmjdrc-2019-001067
38Klonoff DC, Parkes JL, Kovatchev BP, Kerr D, Bevier WC, Brazg RL, et al. Investigation of the Accuracy of 18 Marketed
Blood Glucose Monitors. Diabetes Care. 2018;41(8):1681-8. Epub 2018/06/15. doi: 10.2337/dc17-1960
39
Yu-Fei W, Wei-Ping J, Ming-Hsun W, Miao OC, Ming-Chang H, Chi-Pin W, et al. Accuracy Evaluation of 19 Blood
Glucose Monitoring Systems Manufactured in the Asia-Pacific Region: A Multicenter Study. J Diabetes Sci Technol.
2017;11(5):953-65. doi: 10.1177/1932296817705143
40Bailey TS, Wallace JF, Pardo S, Warchal-Windham ME, Harrison B, Morin R, et al. Accuracy and User Performance
Evaluation of a New, Wireless-enabled Blood Glucose Monitoring System That Links to a Smart Mobile Device. J Diabetes
Sci Technol. 2017;11(4):736-43. doi: 10.1177/1932296816680829
41
Christiansen M, Greene C, Pardo S, Warchal-Windham ME, Harrison B, Morin R, et al. A New, Wireless-enabled Blood
Glucose Monitoring System That Links to a Smart Mobile Device: Accuracy and User Performance Evaluation. J Diabetes
Sci Technol. 2017;11(3):567-73. Epub 2017/07/27. doi: 10.1177/1932296817691301
42Freckmann G, Jendrike N, Baumstark A, Pleus S, Liebing C, Haug C. User Performance Evaluation of Four Blood Glucose
Monitoring Systems Applying ISO 15197:2013 Accuracy Criteria and Calculation of Insulin Dosing Errors. Diabetes therapy: research, treatment and education of diabetes and related disorders. 2018;9(2):683-97. doi: 10.1007/s13300-018-0392-6
43
Jendrike N, Baumstark A, Pleus S, Liebing C, Kamecke U, Haug C, et al. Accuracy of five systems for self-monitoring ofblood glucose in the hands of adult lay-users and professionals applying ISO 15197:2013 accuracy criteria and potential
insulin dosing errors. Curr Med Res Opin. 2019;35(2):301-11. Epub 2018/06/22. doi: 10.1080/03007995.2018.1491832
44Katz LB, Smith A, Cameron H, Setford S, Grady M. 10/10 Accuracy Analysis of a Self-Monitoring Blood Glucose System.
J Diabetes Sci Technol. 2021:1932296821993220. doi: 10.1177/1932296821993220

Regulatory Profile for Glucose Self-monitoring Tools 48

Altering a sample may change its sample matrix and, subsequently, the reliability of measurement
results may be affected. While establishing commutability of samples may be feasible for
manufacturers who will likely use similar measurement technology across their products, it isdifficult for third parties performing independent verification of performance to do so . 45
The FDA requirement for the inclusion of subjects who are naïve to self-monitoring of blood
glucose is seen as a positive aspect of the guidance. This action may provide additional relevant
information about the labelling and/or an intuitively correct handling of the SMBG being
investigated.
The acceptance criteria of ISO 15197 and FDA OTC guidance are comparable in that at least 95%
of measurements shall fall with ±15% of the reference value for glucose concentrations ≥100 mg/dl(5.55 mmol/l). But whereas ISO 15197 allows differences of ±15 mg/dl (0.83 mmol/l) for glucose
concentrations <100 mg/dl (5.55 mmol/l), FDA also requires a maximum deviation of ±15%. Thesestrict criteria set by the FDA are expected to be difficult to fulfil by some SMBG manufacturers. In
addition, FDA requirements below 75 mg/dl are stricter for SMBGs than for point-of-care-testing
systems.
Both ISO 15197 and FDA have defined additional criteria to limit the allowed deviations for the 5%of values not falling within the 15 mg/dl (0.83-mmol/l) or 15% limits (see Table 11 “Acceptancecriteria”). FDA requires in total a minimum of 99% values to be within ±20%. For the systemaccuracy evaluation, ISO 15197 requires at least 99% of values to fall within zones A and B of theconsensus error grid (CEG). 46 This requirement is important because it brings relevance toanalytical claims of accuracy. According to Pfützner et al, 47 it is possible to assess the clinicalaccuracy of a blood glucose value measured by a SMBG using an error grid, as “a description of
the potential clinical outcome associated with basing a treatment decision on this value”. An error
grid maps paired data (results comparing SMBG under investigation with a reference method) andplots these on a grid, known as an error grid. The plotted results then fall into clinical categories(no harm, non-significant harm and significant harm). Thus, this measure of clinical accuracy
focuses on the clinical relevance of the meter results in comparison with analytical accuracy.
Whereas ISO 15197 allows for the exclusion of results, e. g., in cases such as obvious handlingmistakes or if predefined sample stability criteria are missed, all results have to be included in an
evaluation according to the FDA guidance, but results falling outside the defined accuracy limits
must be justified from a clinical point of view.
In addition, in a system accuracy evaluation according to ISO 15197, each of the three reagent lots
has to fulfil the following criteria: ≥95% of values within ±15 mg/dl (0.83 mmol/l) / ±15% at
glucose concentrations <100 mg/dl / ≥100 mg/dl (5.55 mmol/l)). The FDA guidance also requires
testing of three different lots, but separate analysis is not stipulated. As the evaluation is
performed across all three lots, results of one lot with insufficient performance may becompensated by two lots with better performance. Thus, the requirement of the ISO standard
appears to be more robust.
Although ISO 15197 and FDA OTC guidance describe comparable criteria for the reference
measurement devices, the procedures to obtain the comparison values for the evaluation haverelevant differences. ISO 15197 stipulates that at least duplicate measurements of each comparison
sample shall be performed. Moreover, in system accuracy analysis, comparison samples shall betaken before and after sampling for the SMBG measurements, to verify sample stability. Meanvalues calculated from duplicate measurements of both samples are used as comparison values inthe evaluation. According to the FDA OTC guidance, only one comparison sample is taken and45

E.g for reasons such as post-market surveillance or monitoring.

46 Parkes JL, Slatin SL, Pardo S, Ginsberg BH. A new consensus error grid to evaluate the clinical significance of inaccuracies

in the measurement of blood glucose. Diabetes Care. 2000;23(8):1143-8
47 Pfützner, A., Klonoff, D. C., Pardo, S., & Parkes, J. L. (2013). Technical aspects of the Parkes error grid. Journal of diabetes
science and technology, 7(5), 1275–1281. https://doi.org/10.1177/193229681300700517

Regulatory Profile for Glucose Self-monitoring Tools 49

duplicate measurements are optional. The requirement of only one measurement to determine
the reference value in accuracy analysis seems inconsistent with the suggestion of at least four
replicates to establish the glucose concentration in samples intended for interference evaluation
where the specific glucose concentration is not expected to have relevant impact on the study
result.
Apart from system accuracy, both ISO 15197 and the FDA OTC guidance require assessment ofprecision and the influence of endogenous and exogenous substances. Further assessments
include mechanical and electrical safety as well as the need for flex studies, although the level ofdetail with which these assessments are described differs between the standards.

6.2. Continuous glucose monitoring systems - CGMs
Assessment of CGM performance is standardised to a markedly lower degree than that of SMBGs.
There are two notable instances, the CLSI POCT05 guideline Performance Metrics for ContinuousInterstitial Glucose Monitoring, 2nd Edition 48 3, henceforth referred to as POCT05, and the US
FDA’s CGM special controls as described in the FDA approval letter to Dexcom. 49
POCT05 covers, for example, point accuracy, trend accuracy and alarm evaluation in addition totechnical aspects, like signal availability or sensor life. Point accuracy relates to how well individual
CGM results match with results obtained with a comparison method, independent from thecurrent glucose rate of change. One of the recommended metrics is the MARD, which is acommonly used but flawed metric, 50 as well as concurrence tables. Trend accuracy reflects how
well the rate of change in CGM results matches the rate of change in comparison method results.
In an alarm evaluation, true and false alerts, as well as confirmed and undetected events of hypoand hyperglycaemia, are assessed for different alert thresholds.
However, metrological traceability of CGMs covers less than half a page. Metrological traceability
is defined by ISO as follows: “Property of a measurement result whereby the result can be related
to a reference through a documented unbroken chain of calibrations, each contributing to themeasurement uncertainty.” The concept of such traceability is to be able to understand the levelof uncertainty, or in this case, accuracy. Yet the concept of metrological traceability is critical formany devices with a quantitative output. Requirements for traceability are described in theinternational standard ISO 17511:2020 In vitro diagnostic medical devices – requirements forestablishing metrological traceability of values assigned to calibrators, trueness control materials andhuman samples. 51 It is currently impossible to obtain sufficiently large volumes of interstitial fluid,
making “compare like with like” approaches unfeasible. Nevertheless, metrological traceability
could be established, for example, to capillary blood glucose values, 52 since most CGMs areintended to either supplement or even replace conventional SMBG, which is based on capillarysamples.

48Clinical and Laboratory Standards Institute. Performance metrics for continuous interstitial glucose monitoring. 2nd

ed. CLSI guideline POCT05. Wayne, PA. 2020
49http://www.accessdata.fda.gov/cdrh_docs/pdf18/K183206.pdf (Accessed 23 March 2021)
50Kirchsteiger H, Heinemann L, Freckmann G, Lodwig V, Schmelzeisen-Redeker G, Schoemaker M, et al. Performance

Comparison of CGM Systems: MARD Values Are Not Always a Reliable Indicator of CGM System Accuracy. J Diabetes Sci
Technol. 2015;9(5):1030-40
51
International Organization for Standardization. In Vitro Diagnostic Medical Devices - Requirements For Establishing
Metrological Traceability Of Values Assigned To Calibrators, Trueness Control Materials And Human Samples. EN ISO
17511:2020. 2020
52

Freckmann G, Nichols JH, Hinzmann R, Klonoff DC, Ju Y, Diem P, et al. Standardization process of continuous
glucose monitoring: Traceability and performance. Clinica chimica acta; international journal of clinicalchemistry. 2021;515:5-12. Epub 2020/12/29. doi: 10.1016/j.cca.2020.12.025
Regulatory Profile for Glucose Self-monitoring Tools 50

Furthermore, POCT05 does not address the impact of study procedures on performance metrics
like MARD. 53,54,55 The guidance does not provide the detailed requirements for study procedures,and minimum performance criteria are missing as well. Therefore, the level of standardisation
among CGMs that can be achieved by following POCT05 is limited.
The FDA special controls for CGMs define specific minimum performance criteria, based also on
point and trend accuracy. Most of the topics covered by POCT05 are included in these special
controls as well. However, these special controls only apply to products that meet the definitionof the FDA assigned term “iCGMs 56” (note, the FDA definition of iCGM is not restricted to CGMs
that are intermittently viewed, see reference below). According to FDA, “iCGMs are designed toreliably and securely transmit glucose measurement data to digitally connected devices, including
automated insulin dosing systems, and are intended to be used alone or in conjunction with these
digitally connected medical devices for the purpose of managing a disease or condition related toglycaemic control”.35 Thus, CGMs that are intended to supplement, but not replace, conventional
SMBGs do not fall under the CGM designation, and neither do systems that do not transfer datato connected devices.
As is the case for POCT05, the FDA CGM special controls do not address standardisation of study
procedures, so that the reliability of performance metrics cannot be assured.

53Kirchsteiger H, Heinemann L, Freckmann G, Lodwig V, Schmelzeisen-Redeker G, Schoemaker M, et al. Performance

Comparison of CGM Systems: MARD Values Are Not Always a Reliable Indicator of CGM System Accuracy. J Diabetes Sci
Technol. 2015;9(5):1030-40
54Reiterer F, Polterauer P, Schoemaker M, Schmelzeisen-Redecker G, Freckmann G, Heinemann L, et al. Significance andReliability of MARD for the Accuracy of CGM Systems. J Diabetes Sci Technol. 2017;11(1):59-67. doi:
10.1177/1932296816662047
55Heinemann L, Schoemaker M, Schmelzeisen-Redecker G, Hinzmann R, Kassab A, Freckmann G, et al. Benefits andLimitations of MARD as a Performance Parameter for Continuous Glucose Monitoring in the Interstitial Space. J Diabetes
Sci Technol. 2020;14(1):135-50. doi: 10.1177/1932296819855670
56 FDA definition of iCGM for product code QBJ “An integrated continuous glucose monitoring system (iCGM) is intended
to automatically measure glucose in bodily fluids continuously or frequently for a specified period of time. iCGM systems
are designed to reliably and securely transmit glucose measurement data to digitally connected devices, including
automated insulin dosing systems, and are intended to be used alone or in conjunction with these digitally connected
medical devices for the purpose of managing a disease or condition related to glycemic control.”https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm?id=682 Accessed 05/05/2021

Regulatory Profile for Glucose Self-monitoring Tools 51

7. DISCUSSION
This section will take the analysis of current practices and make recommendations that may assist
manufacturers and assessment bodies in ensuring that the SMBGs and CGMs available for use in
LMICs and in other settings are fit for purpose. Recommendations will be made for aspects to beconsidered in the development of any new guidance for these devices. The evolving regulatory
landscape, not only in LMICs, but also in Europe, provides an opportunity to highlight the issues
impacting on performance and also to provide solutions for their mitigation.

7.1. Tools for Improvement: General
ISO 15197 and FDA guidance for over-the-counter SMBGs are intended to be applied when SMBGs
are introduced to the market and, as outlined above, both define numerous requirements
regarding quality of SMBGs. In the last years, however, several independent post-marketing
evaluations of system accuracy showed that a number of the SMBGs available on the Europeanand US markets do not fulfil the respective requirements. 57,58,59
As outlined earlier in this report, efforts have been made towards standardising performanceassessments of CGMs. However, the current status of standardisation can be improved, forexample by addressing unresolved issues. In 2019, a working group on CGM was created by theInternational Federation of Clinical Chemistry and Laboratory Medicine (IFCC) 60,61. The working
group remains active with the work of standardization of CGM performance continuing.
The following recommendations could help to improve the quality of SMBGs and CGMs on themarket.

7.1.1. Verification of performance by the regulatory authority
7.1.1.1. Pre-approval independent verification of performance claims
Although performance must be established by all SMBGs brought to the market, a manufacturerindependent evaluation of the claimed performance of SMBG or CGMs is not mandatory. Thus,
the manufacturer remains the sole generator of performance data. Manufacturer-independent
evaluations before market introduction can help to ensure the quality of available SMBGs andCGMs. A Scandinavian institution supported by the government, the Scandinavian Evaluation ofLaboratory Equipment for Point of Care Testing (SKUP), performs structured SMBG evaluations.
In Norway, for example, an SMBG needs a positive evaluation outcome following testing by SKUP
in order for the product to be reimbursed by health insurance. Similarly, in the EU, all high-riskblood screening tests are required to have independent verification of results by an EU referencelaboratory before market approval, under the forthcoming IVDR.

57

Pleus S, Baumstark A, Jendrike N, Mende J, Link M, Zschornack E, et al. System accuracy evaluation of 18 CEmarked current-generation blood glucose monitoring systems based on EN ISO 15197:2015. BMJ open
diabetes research & care. 2020;8(1). Epub 2020/01/21. doi: 10.1136/bmjdrc-2019-001067
58
Klonoff DC, Parkes JL, Kovatchev BP, Kerr D, Bevier WC, Brazg RL, et al. Investigation of the Accuracy of 18
Marketed Blood Glucose Monitors. Diabetes Care. 2018;41(8):1681-8. Epub 2018/06/15. doi: 10.2337/dc171960
59
Yu-Fei W, Wei-Ping J, Ming-Hsun W, Miao OC, Ming-Chang H, Chi-Pin W, et al. Accuracy Evaluation of 19
Blood Glucose Monitoring Systems Manufactured in the Asia-Pacific Region: A Multicenter Study. J Diabetes
Sci Technol. 2017;11(5):953-65. doi: 10.1177/1932296817705143
60International Federation of Clinical Chemistry and Laboratory Medicine. Working Group on Continuous
Glucose Monitoring (WG-CGM) 2019 [accessed 27 Mar 2020]. Available from: https://www.ifcc.org/ifccscientific-division/sd-working-groups/wg-cgm/
61
Freckmann G, Nichols JH, Hinzmann R, Klonoff DC, Ju Y, Diem P, et al. Standardization process of continuous
glucose monitoring: Traceability and performance. Clinica chimica acta; international journal of clinicalchemistry. 2021;515:5-12. Epub 2020/12/29. doi: 10.1016/j.cca.2020.12.025
Regulatory Profile for Glucose Self-monitoring Tools 52

Inclusion of independent evaluations may be beneficial, not only because of the inherent conflictof interest of testing by the manufacturer influencing claims, but also to detect problems in the
manufacturing process. For example, errors in the calibration of an SMBG or CGM may not be
detected if the manufacturer uses the same study procedures for calibration and for pre-market
performance assessment. As part of best practice, results of this independent testing should be
published.
7.1.1.2. Lot release testing
The performance of an SMBG or CGM relies on evidence generated by the manufacturer before
market introduction. Regular evaluations such as independently organized testing of each new lotof test strip could, therefore, help to ensure continued quality throughout the whole life cycle of
an SMBG. This testing would require use of an accepted reference method (that is, a state-of-theart laboratory-based assay), and the manufacturer would be required to send samples of strips or
sensors from each lot/batch to a reference laboratory before release of that lot to the market.
Such a requirement exists as part of regulatory authorization in the EU and the USA for the highrisk devices used for screening of the blood supply.
Although pre-market confirmation of performance as a condition of regulatory approval aremechanisms usually applied only to the highest risk IVDs, there is a strong argument for theirapplication for SMBGs and CGMs. Three strong reasons support this approach:•According to WHO, 62 diabetes is one of the top 10 causes of death globally. Self-monitoring isa critical tool in the response to this disease, and has the potential, when devices are accurate
and information from the device is acted on appropriately, to significantly reduce mortality
and morbidity. As such, the incidence of this disease should be taken into account in theregulatory risk classification.

•

These devices are used by lay users, whose trust in the results cannot afford to be negatively
impacted due to poorly performing devices. The lay user has far fewer resources at theirdisposal to verify performance than a professional using a glucose measuring device in alaboratory. From a regulatory perspective, this represents a high risk.

•

These medical devices do not come with controls or international standards to confirm theperformance.
As such, the proposals for the additional regulatory interventions listed above is based on a riskbased approach for the identification of appropriate controls.
7.1.2. Standardised reference method
Mass spectrometry-based methods are recognized as reference methods for glucose
concentrations in whole blood and blood plasma. They do not (yet) cover interstitial fluid, which
limits traceability of CGMs (see below). Despite recent development towards easy-to-use
analysers with rapid measuring times, these methods are comparatively expensive and they lackthroughput, so that SMBG and factory-calibrated CGMs are usually calibrated using a laboratory
method. The most common laboratory methods for glucose concentration measurements are
based on enzymatic reactions, implementing glucose oxidase or hexokinase, followed byelectrochemical or photometric principle of detection. These laboratory methods, however, arereported to differ by up to 8%. 63 Even with the same model of laboratory analyser, differences of
up to several percent have been reported. 64 This systematic difference is, for example,
compounded by the tolerance limit of up to ±15 mg/dl (0.83 mmol/l) / 15% difference allowed by
ISO 15197 / FDA OTC guidance.

62https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-

death#:~:text=Leading%20causes%20of%20death%20globally&text=The%20world's%20biggest%20killer%20is,8.9%20
million%20deaths%20in%202019 (Accessed 29 March 2021)
63
Twomey PJ. Plasma glucose measurement with the Yellow Springs Glucose 2300 STAT and the Olympus AU640. Journalof clinical pathology. 2004;57(7):752-4. doi: 10.1136/jcp.2003.013417
64Bailey TS, Klaff LJ, Wallace JF, Greene C, Pardo S, Harrison B, et al. Fundamental Importance of Reference Glucose
Analyzer Accuracy for Evaluating the Performance of Blood Glucose Monitoring Systems (BGMSs). J Diabetes Sci
Technol. 2016;10(4):872-5. doi: 10.1177/1932296816634356

Regulatory Profile for Glucose Self-monitoring Tools 53

ISO 15197 and the FDA OTC guidance have similarly vague requirements for reference
measurement procedures (comparison methods). The reference method has to be traceable andit has to have proven trueness and precision. These requirements, as well as requirements for
CGMs, should be complemented by more specific criteria for allowed bias to reference methods/ reference materials of higher order (e.g., mass spectrometry methods or materials whose
glucose concentration has been assigned by mass spectrometry methods) and precision, in orderto standardise reference methods used for calibration and performance analyses of SMBGs andCGMs. 65
Requirements in quality assurance of IVDs used for healthcare in laboratories do not necessarily
ensure adequate performance of reference methods. In Germany, for example, the external quality
assurance allows deviations of up to ±15% from a target value determined with an isotope dilution
gas chromatography–mass spectrometry method. 66 Although tighter criteria (±6 mg/dl(0.33 mmol/l) or ±10%) are applied in the US, consensus values can be used as target values, andthus, metrological traceability is not adequately considered. 67
In order to establish valid glucose concentrations for the comparison samples, the number of
replicate measurements should be informed by the analyser’s imprecision. However, at least
duplicate measurements should be performed with the comparison method so that erroneous
measurements can be more easily identified. In addition, taking two comparison samples as
required by ISO 15197, one before and one after measurements with the SMBG, enables thedetection of sample stability as well as potential issues with the comparison method.

7.1.3. Clinical impact assessment
This section will look at clinical impact from three perspectives; the first related to the tools at
hand to estimate clinical impact, the second reports on studies of test inaccuracy and the third
looks at potential impacts on self-monitoring devices based on changing clinical guidelines.
7.1.3.1. Revised assessment tools needed
As noted earlier, an error grid is a statistical tool to assess the clinical (as opposed to analytical)
accuracy of a blood glucose value. It describes the potential clinical outcome associated withbasing a treatment decision on a glucose result.
The application of a revised error grid (e.g., surveillance error grid) instead of the outdated
consensus error grid would provide a more precise indication of the clinical impact ofmeasurements errors. According to Klonoff et al, 68 “Currently used error grids for assessing
clinical accuracy of blood glucose monitors are based on out-of-date medical practices. Error
grids have not been widely embraced by regulatory agencies for clearance of monitors, but thistype of tool could be useful for surveillance of the performance of cleared products. The Diabetes
Technology Society, together with representatives from the FDA, the American Diabetes
Association, the Endocrine Society, and the Association for the Advancement of Medical
Instrumentation, and representatives of academia, industry, and government, have developed a
new error grid, called the surveillance error grid as a tool to assess the degree of clinical risk frominaccurate blood glucose monitors”. Compared to traditional error grids, surveillance error grids
are continuous, that is, each point of the grid has its own risk value.

65Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Kirkman MS, et al. Guidelines and recommendations forlaboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2011;57(6):e1-e47
66Bundesärztekammer. Neufassung der Richtlinie der Bundesärztekammer zur Qualitätssicherung

laboratoriumsmedizinischer Untersuchungen – Rili-BÄK. Dtsch Arztebl International. 2019;116(51-52):2422. doi:
10.3238/arztebl.2019.rili_baek_QS_Labor20192312
67https://www.law.cornell.edu/cfr/text/42/part-493 (Accessed 27 March 2021)
68Klonoff DC, Lias C, Vigersky R, Clarke W, Parkes JL, Sacks DB, Kirkman MS, Kovatchev B; ErrorGrid Panel. The surveillanceerror grid. J Diabetes Sci Technol. 2014 Jul;8(4):658-72.

Regulatory Profile for Glucose Self-monitoring Tools 54

7.1.3.2. Clinical impact on the individual and the healthcare system
Although individual measurement errors may have a relevant clinical impact on a specifictherapeutic decision, this might not represent the overall impact of the SMBG’s level of accuracy(or inaccuracy) on long-term therapy management.
Simulation studies have been performed in the past to assess the long-term impact of SMBG
accuracy. 69,70 As expected, the level of accuracy impacted clinical outcomes. In case of negative
bias (systematic measurement difference), glycated haemoglobin (HbA1c) readings tended toincrease, whereas positive bias was associated with lower HbA1c readings and increased risk forsevere hypoglycaemia. Higher levels of imprecision also tended to increase risk for severe
hypoglycaemia. This decrease in quality of glucose control was associated with higher healthcare
costs.
For CGMs, the same relationship can be expected, although it has not been studied in such detail.
For example, considerable systematic differences were found between systems in the low glucose
concentration range, 71 and therapeutic parameters derived from CGMs were found to differ inhead-to-head settings. 72,73
Although SMBGs sold in Europe or the US should provide sufficiently accurate results, this is notalways the case. 74,75 Therefore, the lack of analytical accuracy likely still has a relevant impact on
healthcare costs. Whether the additional financial burden will outweigh any potential pricedifference between insufficiently and sufficiently accurate SMBGs would have to be assessed
separately for different countries. According to anecdotal reports, newer-generation SMBGs are
sold in LMICs only after considerable delay, and third-party strips with questionable accuracy
might be more prevalent there. If these reports were confirmed to be true on a relevant scale,
additional efforts would likely have to be made to ensure access to an adequate level of diabetes
therapy.
7.1.3.3. Impact of changing clinical guidelines
A current concern of experts has the potential to ultimately impact management of diabetes in
LMICs. HbA1c is seen as the gold standard with regards to monitoring the treatment regimen of
people with diabetes. Limitations of this measure are that it provides an average of blood glucose
levels over a period of a few months with the argument being that an individual with periods ofhigh and low blood glucose levels may have an average that is similar to someone who has a moreconstant level. In the last three to four years, with new CGMs coming to market, the concept of“time in range” has gained traction. This concept looks at the time the individual spends below or
above a given range of blood glucose levels. These have been defined as 70–180 mg/dL (3.9–10.0
mmol/L) for individuals with type 1 diabetes and 63–140 mg/dL (3.5– 7.8 mmol/L) for people with
type 2 diabetes.

69Campos-Nanez E, Fortwaengler K, Breton MD. Clinical Impact of Blood Glucose Monitoring Accuracy: An In-Silico Study.

J Diabetes Sci Technol. 2017;11(6):1187-95. Epub 2017/06/02. doi: 10.1177/1932296817710474
70Fortwaengler K, Campos-Nanez E, Parkin CG, Breton MD. The Financial Impact of Inaccurate Blood Glucose Monitoring

Systems. J Diabetes Sci Technol. 2018;12(2):318-24. doi: 10.1177/1932296817731423
71Fokkert MJ, van Dijk PR, Edens MA, Abbes S, de Jong D, Slingerland RJ, et al. Performance of the FreeStyle Libre Flashglucose monitoring system in patients with type 1 and 2 diabetes mellitus. BMJ open diabetes research & care.
2017;5(1):e000320. Epub 2017/03/01. doi: 10.1136/bmjdrc-2016-000320
72
Michalak A, Pagacz K, Mlynarski W, Szadkowska A, Fendler W. Discrepancies between methods of continuous glucose
monitoring in key metrics of glucose control in children with type 1 diabetes. Pediatr Diabetes. 2019;20(5):604-12. doi:
10.1111/pedi.12854
73Freckmann G, Pleus S, Schauer S, Link M, Jendrike N, Waldenmaier D, et al. Choice of Continuous Glucose Monitoring
Systems May Affect Metrics: Clinically Relevant Differences in Times in Ranges. Exp Clin Endocrinol Diabetes. 2021. Epub
2021/01/30. doi: 10.1055/a-1347-2550
74
Pleus S, Baumstark A, Jendrike N, Mende J, Link M, Zschornack E, et al. System accuracy evaluation of 18 CE-marked
current-generation blood glucose monitoring systems based on EN ISO 15197:2015. BMJ open diabetes research & care.
2020;8(1). doi: 10.1136/bmjdrc-2019-001067
75Klonoff DC, Parkes JL, Kovatchev BP, Kerr D, Bevier WC, Brazg RL, et al. Investigation of the Accuracy of 18 Marketed
Blood Glucose Monitors. Diabetes Care. 2018;41(8):1681-8. Epub 2018/06/15. doi: 10.2337/dc17-1960

Regulatory Profile for Glucose Self-monitoring Tools 55

With the use of this metric gaining prominence in the scientific literature, the concern is that only
continuous monitoring tools can measure time in range and that this will have an impact on theuse of blood glucose meters which only provide a snapshot of blood glucose levels. This is ofimportance in clinical practice, especially in countries where the price of CGMs is prohibitive.
With EU regulation requiring evidence of state of the art in medicine for CE marking, SMBGs may
potentially no longer qualify as a state-of-the-art method for self-monitoring. For the many
countries that accept CE marking as the main regulatory reliance mechanism, this could
potentially result in a lack of supply. Beyond this potential impact on the market, some would
argue more is needed with regards to the impact both on the individual and the provider side ofhaving 24 hours/day 365 days/year of information to manage, analyse and act upon. The
psychological impact of this burden needs to be considered in the manufacturer’s risk benefit
analysis. This complex situation provides a ripe environment for innovation and invention. As withmany non-communicable diseases, the tsunami is silently arriving and gathering force, and timeis of the essence to provide alternative, affordable and quality solutions.

7.1.4. Adverse event reporting
People with diabetes using self-monitoring devices should be encouraged to report problems not
only to their source of strips or sensors (e.g., product distributors), but also to the regulatory
authorities. There is a lack of knowledge of both the availability and the utility of this feedback
mechanism. Device labelling should always make the user aware of their right to report. In
addition, databases held by regulators should be easy to access and should provide useful
information relating to performance problems. The FDA’s MAUDE database and TPLC searches
are considered good examples.
In addition, requirements within regulation, as are being introduced in the EU Regulations, should
enhance legal responsibilities of importers, suppliers and distributors to report problems back to
the manufacturer and to cooperate with enquiries relating to product safety and performance tothe regulatory authorities.

7.1.5. Substandard and falsified devices
Under-reporting of adverse events is always a challenge to understanding the real safety profile
of a medical device. This is a problem in high-income countries, but very little is known of thequality of self-monitoring devices in LMICs. Many LMICs do not have strong regulation of devices
and little capacity to act in the post-marketing setting, even if they are using reliance mechanisms
for pre-market. As such, they are highly vulnerable to receiving substandard products.
Furthermore, there are a number of technical specificities associated with reporting adverse
events in LMICs that make under-reporting an even greater issue. These include how and to whom
to report, and using what means, e.g., mobile phone or app, to a general physician or to a hospitalor to the regulator. Language also becomes a problem with reporting, with most manufacturer
lead-reporting mechanisms only being suitable for English.
As noted earlier, counterfeit and substandard devices are a grave concern in all jurisdictions.
Regardless of the stringency of regulatory oversight, criminal activity will endure. Anecdotally,
lot/batch dumping by manufacturers of strips that do not meet the performance standards
expected for sale in well-regulated settings has been reported. It is hoped that the prevalence issignificantly curbed with current regulatory measures to ensure greater traceability andtransparency such as the introduction of the UDI. In the meantime, a study is urgently warranted
to understand in some manner the extent of substandard and falsified product in the market in
LMICs.

7.1.6. Specific requirements in LMICs
Self-monitoring of blood glucose in LMICs may be associated with additional requirements forvalidation of SMBG or CGMs. Many SMBG and CGMs are geared towards use in the market for
which they were developed, e.g., Europe or the US, with distinct purchasing power, andspecificities in climate, nutrition, co-morbidities and level of user education, etc.

Regulatory Profile for Glucose Self-monitoring Tools 56

Test strip shelf-life, as well as measurement performance, are typically affected by both high andlow temperatures as well as relative humidity. Storage of reagents (e.g., test strips) at room
temperature is easier in temperate climates or if air conditioning is available, whereas dry storage
might be a challenge in the tropics. Performing control solution tests may indicate whether the
specific test strip lot is still viable. However, at least in the US and EU, control solution tests are
rarely performed. 76
Manufacturers of SMBGs and CGMs must undertake interference testing according to both ISO
15197 and FDA’s OTC guidance using a risk-based approach. This testing investigates whether theaccuracy of the test is influenced by interfering factors, that is, chemicals or proteins that may
impact test performance. The base list of substances in these guidances does not cover a numberof important potential factors to be considered when the product is used outside of a high-income
setting. For instance, the potential interfering impact of antiretroviral or antimalarial medication
should be tested where the strips are intended for Africa. The decision is left to manufacturers totest for relevant additional medication.
A potential issue in LMICs can be literacy. If measurements are intended to be performed byindividuals with diabetes themselves, the complexity of instructions for use should be geared
specifically to the intended users. Specific or extensive training and education in the use of SMBG
and CGMs might be a helpful approach, as well as redesign of instructions for use, or the creationof job aids, all undertaken under the control of the manufacturer.
Another approach to monitor and assure quality is through the organisation of a centralised lot
release scheme at the medical goods storehouse. In situations where the level of infrastructure
available at the specific testing site might prohibit the use of a large laboratory analyser, smaller
bench-top analysers or even high-quality hand-held over the counter or point-of-care blood
glucose meters might provide sufficiently reliable results, or samples might be processed on-site
but then shipped for centralised measurement. 77
It seems pragmatic to use a risk-based approach for individual countries or regions to identify
shortcomings of current standards that are relevant for the specific country or region. Such efforts
could be made internationally since some overlap can be expected.

7.2. SMBGs
7.2.1. Adjusted protocols
As described above, the comprehensive pre-marketing evaluations as described by ISO 15197 or
the FDA guidance should be complemented by regular post-marketing evaluations to ensure
continued quality of SMBGs. Furthermore, reporting of all measured values, as intended by FDA
guidance, could be beneficial for making an informed decision during approval of SMBGs. Thereis value if the performance is verified by an independent laboratory using protocols established bysubject matter experts. The need for this is highlighted by the practice of some manufacturers tocompare capillary SMBG results with those from venous comparison samples. This practice canlead to deviations independent from the quality of the assessed SMBG. 78,79 Accuracy studies should
focus on like-with-like comparisons. If the system is intended to be used with capillary samples,the comparison samples should also be capillary blood.

76Heinemann L. Control Solutions for Blood Glucose Meters: A Neglected Opportunity for Reliable Measurements? J
Diabetes Sci Technol. 2015;9(4):723-4. doi: 10.1177/1932296815587602
77Pleus S, Freckmann G, Baumstark A, Haug C. Stability of Glucose Concentrations in Frozen Plasma. J Diabetes Sci
Technol. 2020:1932296820963657. doi: 10.1177/1932296820963657
78Choukem SP, Sih C, Nebongo D, Tientcheu P, Kengne AP. Accuracy and precision of four main glucometers used in a
Sub-Saharan African Country: a cross-sectional study. The Pan African medical journal. 2019;32:118. doi:
10.11604/pamj.2019.32.118.15553
79Freckmann G, Pleus S, Baumstark A. Comment on "accuracy and precision of four main glucometers used in a subSaharan African country: a cross-sectional study" by Choukem et al. The Pan African medical journal. 2019;33:271. doi:
10.11604/pamj.2019.33.271.19704

Regulatory Profile for Glucose Self-monitoring Tools 57

Independent performance evaluations do not necessarily have to implement the complete ISO
15197 or FDA OTC protocols, but could instead use reduced-scale protocols focusing on the most
relevant performance metrics. For example, a system accuracy evaluation in which at least
duplicate measurements are performed from subject samples would simultaneously allow for
estimation of precision based on variability within the replicates across subjects. With higher
numbers of replicates, this estimate could be improved. Two or more independent lots of devices
should be used in such a study.
Hematocrit influence could be estimated as well, at least for the range spanned by the subject
samples. This estimate could be based on a regression line, or hematocrit values could be
categorised, and average values could be calculated for each category. If the numbers of samples
in specific glucose concentration categories were pre-defined at least for the majority of samples,
this could help make performance assessments easier to compare, especially if SMBGs exhibit
concentration-dependent performance.
Reduced-scale protocols certainly do not allow drawing conclusions with the same level ofstatistical confidence as the full-scale protocols, 80 because the number of independent samples isreduced. Nevertheless, such evaluations could allow conclusions to be drawn regarding changes
in accuracy from one evaluation to the next, so that the effort associated with performing fullscale protocols would not be required for release of every reagent lot.
A reduced-scale standardised protocol could also help countries in performance evaluation oftender bidders, when making large-scale tender purchase decision.

7.3. CGMs
7.3.1. Metrological traceability
Neither POCT05 nor the FDA CGM special controls adequately address metrological traceability.
Establishing metrological traceability for CGMs, at least in the conventional sense as per ISO 17511,
is currently impossible, because interstitial fluid, where CGMs measure glucose concentrations,cannot be obtained in sufficiently large volumes over a sufficiently short time. Furthermore, noreference methods, i.e., methods of highest metrological order, are currently available forinterstitial fluid. 81
Most CGMs are intended to supplement or replace conventional SMBG in home use by people
with diabetes. Comparing CGM measurement results with SMBG measurement results might bean adequate way forward until other methods become available. Due to physiologic differences ininterstitial and capillary blood glucose concentrations, many CGMs use algorithms to model, andcorrect for, these differences so that capillary glucose concentrations are approximated. This
results in such CGMs displaying glucose values that are neither directly comparable to interstitial
nor capillary glucose concentrations.
As long as manufacturers clearly indicate how measurement signals are converted to CGM values,a basic level of traceability could be established, even if this resulted in comparably high levels of
uncertainty. 82

Klonoff DC, Lias C, Beck S, Parkes JL, Kovatchev B, Vigersky RA, et al. Development of the Diabetes Technology Society
Blood Glucose Monitor System Surveillance Protocol. J Diabetes Sci Technol. 2016;10(3):697-707. doi:
10.1177/1932296815614587
81Joint Commitee for Traceability in Laboratory Medicine. Database of higher-order reference materials, measurement
methods/procedures and services 2015 [accessed 11-Mar-2021]. Available from:http://www.bipm.org/jctlm/viewResults.do?type=isRMP&searchString=Glucose&searchStringIUPAC=&searchStringMi
xed=&analyteCategory=&matrixCategory=&uniqueNominationNumber=&sortBy=Analyte_Name&status=P&id=C3RMMP1
9*1*10&id=NRMeth+4*2*10&x=22&y=982Freckmann G, Nichols JH, Hinzmann R, Klonoff DC, Ju Y, Diem P, et al. Standardization process of continuous glucose
monitoring: Traceability and performance. Clinica chimica acta; international journal of clinical chemistry. 2021;515:5-12.
doi: 10.1016/j.cca.2020.12.02580

Regulatory Profile for Glucose Self-monitoring Tools 58

7.3.2. Study procedures
As described earlier, study procedures can impact performance metrics like MARD. 83,84,85 By
stipulating detailed requirements for study procedures, this effect could be mitigated to somedegree. For example, the time delay between changes in interstitial and capillary glucose
concentrations is more pronounced when glucose concentrations are rapidly changing. Insulintreated people with diabetes tend to exhibit larger glucose variability than people with diabetes
who are not on insulin therapy. Participants in clinical studies should include the intended use
population, and if substantial differences in the performance are expected, subgroups should be
sufficiently large to be analysed separately.

7.3.3. Other requirements
Quality assurance in general might be a bigger issue with CGMs than with SMBGs. Whereas SMBGs
are IVDs, measuring samples outside of the body, CGMs measure glucose concentrations in vivo.
Traditional quality assurance schemes by users are therefore not applicable; sensors of CGMs
cannot be removed from the body for control measurements and then reinserted. Still, quality
assurance by the user would be beneficial since it would reflect performance under actual use
conditions.

83Kirchsteiger et al. Performance Comparison of CGM Systems: MARD Values Are Not Always a Reliable Indicator of CGM

System Accuracy. J Diabetes Sci Technol. 2015 Sep 1;9(5):1030-40.
84Reiterer et al Significance and Reliability of MARD for the Accuracy of CGM Systems J of Diabetes Sci Technol. 2017, Vol.
11(1) 59–67
85Heinemann et al. Benefits and Limitations of MARD as a Performance Parameter for Continuous Glucose Monitoring in
the Interstitial Space. J Diabetes Sci Technol. 2020 Jan;14(1):135-150

Regulatory Profile for Glucose Self-monitoring Tools 59

8. RECOMMENDATIONSThis section will take the analysis of current practices and make recommendations that may assist
manufacturers and assessment bodies in ensuring that the SMBGs and CGMs are fit for purpose.
It is hoped that these findings will assist regulators and others involved in the evaluation of thesedevices. The evolving regulatory landscape, not only in LMICs but also in Europe, provides anopportunity to highlight the issues impacting on performance and provides solutions for their
mitigation.
Recommendations:8.1. Effective implementation of regulations
The majority of regulatory agencies globally use reliance mechanisms based on CE marking
and/or FDA approval to allow market access of SMBGs and CMGs. Thus, it is critical that theassessment that results in a CE mark or a 510 (k) approval is based on application of appropriate
standards by manufacturers and pre-market assessment by those with an in-depth understandingof the science behind the devices. The standards that are recognised for the purposes ofdemonstrating conformity to the performance requirements of the regulation must haveinternational consensus as being the most appropriate for these devices. The manufacturer must
comprehensively demonstrate conformity to these standards, and the CAB must ensure that those
assessing the technical and clinical evidence are competent for this task. (Refer to IMDRF“Competence and Training Requirements for Regulatory Authority Assessors of Conformity
Assessment Bodies Conducting Medical Device Regulatory Reviews” IMDRF/GRRP
WG/N63FINAL:2020). The requirements for competence of notified body assessors should,
according to the new regulations in the EU, mitigate problems identified under the Directives that
resulted in CE certificates issued without sufficient evidence that the device would perform as
intended.
Achieving consistency with the validation of these important devices requires agreement
regarding the pre-analytical, analytical, clinical and user assessments that should be undertakenby the manufacturer. Greater harmonisation of guidance (for instance with the requirements of
ISO and FDA guidance) can achieve this. Further consistency could be achieved if an international
standard is created for CGMs that is then recognised by all jurisdictions. In addition, requirements
for reporting of verification and validation studies could be harmonised internationally to enable
ready comparison of data from different sources.
In the absence of any mandatory inspection activities carried out for an FDA issued 510 (k)notification, further post-marketing reporting mechanisms, such as those required for the IVDR
and MDR in the EU, may strengthen confidence in devices where market access relies on US FDA
authorisation.

8.2. Enhanced post-market activities by manufacturers
Manufacturers of SMBGs should enrol their device in appropriate External Quality Assessment
Schemes, even if these schemes are provided for laboratory-based devices. The results should
form part of their post-market performance surveillance and of any updates to the clinicalperformance report.

8.3. Understanding the critical impact of temperature and humidity on
performance of SMBG strips
The critical negative influence of factors including humidity and temperature means that, for
SMBG strips, manufacturers selling in countries with extremes of these environmental factors
should ensure that the strips have been designed to be robust in extreme conditions. Warnings
relating to storage conditions should be apparent.

Regulatory Profile for Glucose Self-monitoring Tools 60

The CAB assessing stability must understand the importance of appropriately designed stability
studies, including transport stability. WHO guidance, EXPERT COMMITTEE ON BIOLOGICALSTANDARDIZATION Technical Guidance Series for WHO prequalification of in vitro diagnostic
medical devices Establishing stability of in vitro diagnostic medical devices–TGS-2 and Annex to TGS
2 Establishing component stability for in vitro diagnostic medical devices can be considered bestpractice for this purpose.

8.4. LMICs activities in the absence of strong in-country regulation
For many LMICs, a lack of a strong regulatory agency poses a high level of risk of substandard
devices being made available. However, there are a number of ways that LMICs can amelioratethat risk.

8.4.1. Survey of quality of self-management devices on the LMIC market
Although it is assumed that the lack of strong regulation in many LMICs will mean that a
proportion of devices for self-management of diabetes currently on these markets may besubstandard, it is important that empirical evidence of this is sought. The size and nature of the
problem needs to be understood before effective countermeasures can be put in place.

8.4.2. Recognition and Reliance
Where there is a legal framework, LMICs should ensure that there is the possibility to recognise
and leverage the efforts of mature regulatory agencies. It is highly recommended that devices for
self-management of diabetes be either CE marked or have FDA authorisation. Consideration canbe given to decisions of other regulatory agencies; however, a comprehensive understanding of
the decision-making process by the agency should be made beforehand to understand the extent,
if any, of pre-market assessment and requirements for these devices. Once WHO Prequalificationof SMBGs commences, recognition of the assessments carried out by this body should also be
added as an alternative requirement.

8.4.3. Pre-distribution QC activities
In LMICs, the majority of medical products for use via the public sector come into the country andare placed in a central medical store (CMS) before further distribution. At this point, lot verification
activities should be encouraged for SMBG strips. The CMS would require a point of care
instrument capable of measuring glucose with a high level of accuracy. Such instruments can be
identified through results in External Quality Assessment Schemes and through the peerreviewed scientific literature. This would be deployed to prepare and quantitate glucose in fresh
blood samples for testing new batches of SMBG strips. Development of a standardised lot
verification protocol that can be implemented easily at the country level would be beneficial.

8.4.4. Assuring temperature-controlled supply of SMBG strips
Taking into account the labile nature of SMBG strips, all efforts should be made to ensure that the
strips are stored properly, according to the conditions noted on the labels. This requirement will
not be unique to SMBG components, as many rapid tests supplied to LMICs have similar issues,
relying on maintenance of cold room storage to ensure adequate performance. All stakeholders inthe supply chain, and the end user, need to be aware of the importance of this.

8.5. UDI and Increased stakeholder awarenessImplementation of the UDI by regulatory authorities will result in significant benefits for all
stakeholders as it becomes a requirement in an increasing number of jurisdictions. For people
living with diabetes, they will be able to access more information regarding their device. UDI
assists in understanding the provenance of a device, providing a strong mechanism to ensure adevice is from the manufacturer on the label. For distributors, the ability to electronically scanlabels and devices provides a powerful tool to efficiently manage inventory, reduce manual errors
and improve better delivery. For the manufacturer, benefits include better traceability andefficiency in recalls and improved quality of information through the use of a standardised data
model across the industry. For the regulator, the benefits are similar to that for industry.
Regulatory Profile for Glucose Self-monitoring Tools 61

8.6. Enhancing awareness of regulatory support in people living with diabetes
The importance of reporting problems in device performance to the regulator is often
underestimated or even not known by end users. It is important that people living with diabetes
are aware that they can report any concerns regarding the safety or performance of their selfmonitoring device to both the manufacturer and the regulator. Regulatory bodies rely on passive
reporting of problems in the market. For these agencies, it is important that problems are reported
as these are used by the regulator to identify issues which might not have been previously known
about. The regulator then reviews the issue and, if necessary, can take action to minimise risk andmaximise benefit to patients. Even lack of clarity of the instructions for use is an issue that requires
reporting. This can be a significant issue in countries where translations of original instructions
are required.

8.7. Reference Institutions
The establishment of national or supranational reference institutions with competence to assess
devices for self-monitoring would be helpful to ensure sustained quality of SMBGs or CGMs 86,87. It
is likely that certain laboratories will be chosen to support WHO Prequalification, via acomprehensive assessment of the laboratory’s ability to undertake specific reference activities inthis area. The establishment of WHO collaboration centres for devices used with diabetes may be
one avenue that would attract the necessary support to sustain such centres of excellence.
Regulatory authorities can also create formal ties with such institutions.

86Heinemann L, Freckmann G, Koschinsky T. Considerations for an Institution for Evaluation of Diabetes Technology

Devices to Improve Their Quality in the European Union. J Diabetes Sci Technol. 2013;7(2):542-7
87Freckmann G, Pleus S, Heinemann L, Koschinsky T. Regulatorische Defizite bei Medizinprodukten. Der Diabetologe.

2016;12(8):558-65. Epub 2016/11/28. doi: 10.1007/s11428-016-0158-6

Regulatory Profile for Glucose Self-monitoring Tools 62

9. APPENDIX 1. REGULATION OF DEVICES BY THE UNITEDSTATES OF AMERICA FOOD AND DRUG ADMINISTRATION
9.1. Overview of regulation of devices within FDA
Within the FDA, medical devices are regulated under the same regulatory schemes as IVDs. There
are two centres for evaluation of medical devices: the Centre for Biological Evaluation andResearch (CBER); and the Center for Devices and Radiological Health (CDRH). CBER is the centre
within FDA that regulates biological products for human use and devices used for blood screening
and associated activities are assessed in this branch. The majority of devices fall under the auspicesof CDRH, responsible for regulating firms who manufacture, repackage, relabel, and/or import
medical devices sold in the US.
Medical devices in the US are classified into Class I, II, and III. Regulatory control increases fromClass I to Class III. The device classification regulation defines the regulatory requirements for ageneral device type. Most Class I devices are exempt from Pre-market Notification 510(k); mostClass II devices require Pre-market Notification 510(k); and most Class III devices require Premarket Approval.
The basic regulatory requirements that manufacturers of medical devices distributed in the U.S.
must comply with are:• Establishment registration• Medical Device Listing• Pre-market Notification 510(k), unless exempt, or Pre-market Approval (PMA)• Investigational Device Exemption (IDE) for clinical studies• Quality System (QS) regulation• Labeling requirements• Medical Device Reporting (MDR)

9.1.1. Pre-market notification 510(k)Most devices that are regulated in the USA are subject to a 510(k) pre-market submission made to
FDA to demonstrate that the device to be marketed is as safe and effective, that is, by proving tobe substantially equivalent to a legally marketed device. Submitters must compare their device toone or more similar legally marketed devices and make and support their substantial equivalence
claims. The legally marketed device(s) to which equivalence is drawn is commonly known as the"predicate." Although devices recently cleared under 510(k) are often selected as the predicate towhich equivalence is claimed, any legally marketed device may be used as a predicate.
A device is substantially equivalent if, in comparison to a predicate it:• has the same intended use as the predicate; and• has the same technological characteristics as the predicate;or has the same intended use as the predicate; and• has different technological characteristics and does not raise different questions of safety
and effectiveness; and• the information submitted to FDA demonstrates that the device is as safe and effective as thelegally marketed device. 88
If novel features of the device determine that substantial equivalence cannot be demonstrated,then the device will require a different pre-market pathway such as the de novo pathway.
9.1.1.1. Requirements for 510 (k)Compliance with 21 CFR 820 is required for Class II devices in the US. However, the FDA does not
usually undertake an on-sight audit to confirm compliance at time of application. Instead, the88 https://www.fda.gov/medical-devices/premarket-submissions/premarket-notification-510k (Sourced 06 Jan 2021)

Regulatory Profile for Glucose Self-monitoring Tools 63

manufacturer submits evidence of a compliant quality system. This may include an ISO 13485:2016
certificate or a Medical Device Single Audit Program (MDSAP) 89 certificate as evidence ofcompliance. This certificate must be submitted with a 510(k) application.
There are currently several pathways available for devices that require a 510(k) clearance,
including a traditional 510(k) pathway or an abbreviated pathway. The Abbreviated 510(k) Program
uses guidance documents, special controls, and/or voluntary consensus standards to facilitate
FDA’s pre-market review of 510(k) submissions. FDA believes that its review of abbreviated 510(k)s
may be more efficient than that of traditional 510(k) submissions. This pathway provides an optionof facilitated review of 510(k)s through a reliance on “summary reports” that briefly describe andsummarise the testing performed to support the submission as recommended in relevant
guidance document(s). 90
Devices that have 510(k) clearance are, in general, obliged to have applied the unique device
identifier (UDI) labelling to the product.

9.2. FDA regulation overview of SMBGs
From a search of relevant data bases, the following FDA details will apply to self-testing blood
glucose monitoring systems and their components:
Regulation Number

CFR 862.1345 Glucose test system“Identification. A glucose test system is a device intended to measure
glucose quantitatively in blood and other body fluids. Glucose
measurements are used in the diagnosis and treatment ofcarbohydrate metabolism disorders including diabetes mellitus,
neonatal hypoglycemia, and idiopathic hypoglycemia, and of
pancreatic islet cell carcinoma.”

DeviceBlood Glucose

Regulation Description

Clinical Chemistry

Product Codes

NBW: System, Test, Blood Glucose, Over The Counter
LFR: Glucose Dehydrogenase, Glucose
CFR: Hexokinase, Glucose
CGA: Glucose Oxidase, Glucose

CPT Code
Waiver)

(For

CLIA

82962 “Blood glucose by glucose monitoring devices cleared by the
FDA for home use.”

Pre-market Review

Office of In Vitro Diagnostics and Radiological Health

Submission Type510(k)Classification

Class II

GMP Exempt?

No

RecognisedStandards

89

Consensus

7-284 CLSI EP37 1st Edition “Supplemental Tables for Interference
Testing in Clinical Chemistry”
7-301 CLSI GP42 7th Edition“Collection of Capillary Blood Specimens”
13-88 IEEE ISO 11073-10417 Third edition 2017-04“Health informatics - Personal health device communication - Part
10417: Device specialization - Glucose meter”

https://www.fda.gov/medical-devices/cdrh-international-programs/medical-device-single-audit-program-mdsap (Sourced 22 Feb 2021)

90 The Abbreviated 510(k) Program Guidance for Industry and Food and Drug Administration Staff Issued 13/09/2019.

Regulatory Profile for Glucose Self-monitoring Tools 64

13-90 IEEE Std_11073-10417-2015“Health Informatics - Personal Health Device Communication, Part
10417: Device Specialization - Glucose Meter”
7-284 CLSI EP37 1st Edition“Supplemental Tables for Interference Testing in Clinical Chemistry”
7-301 CLSI GP42 7th Edition“Collection of Capillary Blood Specimens”
13-88 IEEE ISO 11073-10417 Third edition 2017-04“Health informatics - Personal health device communication - Part
10417: Device specialization - Glucose meter”
13-90 IEEE Std_11073-10417-2015“Health Informatics - Personal Health Device Communication, Part
10417: Device Specialization - Glucose Meter”

9.2.1. Regulatory requirements — general controls for Class II devices
Class II devices are subject to the following regulatory requirements known as “General
Controls”, including but not limited to those governing:
•
•
•
•
•
•
•

Adulteration/Misbranding
Electronic Establishment Registration
Electronic Device Listing
Pre-market Notification [510(k)]Quality Systems, including design control
Labeling, andMedical Device Reporting (MDR).

Although not included as a consensus standard, the FDA guidance Self-Monitoring Blood Glucose
Test Systems for Over-the-Counter Use Sept 2020 provides a detailed description of FDA’s
expectations for a manufacturer’s design verification procedures and the validation of
performance by the intended users.

9.3. FDA regulation of Continuous Glucose Monitoring Systems (CGMs)
CGMs usually consist of a glucose sensor, a transmitter, and a primary receiver. The device
contains software to calculate glucose values. Until 2018, CGMs were classified at the highest risk
class, Class III. Class III devices require the highest level of pre-market oversight by the FDA: a
Pre-market Approval (PMA). The first FDA approved its first CGM—the Minimed Continuous
Glucose Monitoring System—in 2000. In the intervening years, not only was more experience
gained with these devices, but the devices themselves evolved to a point where the mix of both
known risk profile and better design resulted in the down-classification of the devices to a Class
II in 2018 with a fifth-generation CGM. These fifth-generation systems are factory calibrated andno longer require user calibrations, whereby self-monitoring of blood glucose fingerstick values
via a home blood glucose meter is required to correlate the sensor signal with a patient’s blood
glucose value. Note: some CGMs may, due to specific attributes, fall into the higher risk class, ClassIII.
Unlike SMBGs that can be sold in the US over the counter, these products are only available byprescription.

9.3.1. FDA Regulation Overview of CGMs
The following applies to CGM systems for the US FDA:

Regulatory Profile for Glucose Self-monitoring Tools 65

Regulation Number

862.1355

DeviceIntegrated Continuous Glucose Monitoring System, Factory
Calibrated

Definition

An integrated continuous glucose monitoring system (iCGM) is
intended to automatically measure glucose in bodily fluids
continuously or frequently for a specified period. iCGM systems aredesigned to reliably and securely transmit glucose measurement
data to digitally connected devices, including automated insulin
dosing systems, and are intended to be used alone or in
conjunction with these digitally connected medical devices for the
purpose of managing a disease or condition related to glycemic
control.

Physical State

Glucose sensor, a transmitter, and a primary receiver. The device
contains software to calculate glucose values.

Technical Method

A transcutaneous glucose sensor that is factory calibrated. The
sensor is inserted at home by the end user and is used inconjunction with the associated transmitter and receiver tomonitor glucose levels for the management of diabetes.

Product Code

QBJ
QLG

Pre-market Review

Office of In Vitro Diagnostics and Radiological Health (OIR)

Submission Type510(k)

Device Class

II with Special controls

GMP Exempt?

No7-209 CLSI POCT05-A*(Replaces
POCT05-P)
Performance Metrics for Continuous Interstitial Glucose
Monitoring; Approved Guideline.
13-72 IEEE Std
11073-10425-2014
Health informatics - Personal health device communication, Part
10425: Device Specialization - Continuous Glucose Monitor (CGM)

Recognised
standards

consensus
13-88 IEEE ISO 11073-10417
Third
edition2017-04
Health informatics - Personal health device communication - Part
10417: Device specialization - Glucose meter13-90 IEEE Std
11073-10417-2015
Health Informatics - Personal Health Device Communication, Part
10417: Device Specialization - Glucose Meter

Regulatory Profile for Glucose Self-monitoring Tools 66

13-95 IEEE ISO 11073-10425
First
edition2016-06-15
Health informatics - Personal health device communication - Part
10425: Device specialization - Continuous glucose monitor (CGM)* NOTE: The latest version of this CLSI standard was published in November 2020. It is not yet
recognised as a consensus standard.
Of interest, even though the sensor would be considered by GHTF/IMDRF definitions as a medical
device, for the FDA this type of device is only considered an implantable device if it rests in the
body for 30 days or more. If not considered implantable, it is assessed by the Office of In Vitro
Diagnostics and Radiological Health (OIR) and reviewed by the clinical chemistry section of thisoffice. Despite this, the assessment applied recognises the essential principles that are applied to
implantable devices.

9.3.2. Regulatory Requirements
The general regulatory requirements for Class II devices noted above for SMBGs apply equally to
CGMs. However, CGM systems bring new risks that require evidence of mitigation.
A letter from the FDA to an applicant making the first application to the agency of a fifthgeneration CGM system, lists the controls to be applied to successfully be approved by the FDA 91.

91 https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN170088.pdf Sourced 10 February 2021

Regulatory Profile for Glucose Self-monitoring Tools 67

10. APPENDIX 2. REGULATION OF DEVICES IN THE EU
10.1. The regulatory framework in the EU
In comparison with the FDA, where the efforts of the regulatory approval system are placed on
efficacy of a device compared to a predicate, the EU regulatory framework for all medical devices(including IVDs) places an emphasis on whether a device can safely perform its intended function
and whether it is considered state-of-the-art. Also, the regulatory framework is applied in otherways.
The EU regulatory frameworks for medical devices and IVDs aim to provide a more agile
mechanism for pre-market approval, by use of designated certification bodies that are responsible
for pre-market assessment. These bodies are referred to as “notified bodies”. They are private
entities, but designation as such occurs under the control of the European Commission. A
manufacturer directly engages the notified body of choice. As these bodies are for-profit, fee forservice is paid.
Following approval by a notified body, the manufacturer may apply the CE mark to their product.
The efforts of the competent authority (government regulatory agency in each Member State) arein the designation of the notified bodies and for market vigilance. Each competent authority canalso issue derogations from aspects of the regulations in the case of a public health emergency, as
has happened with the COVID-19 pandemic.
Although this system of notified bodies has provided manufacturers with faster approval times,
the lack of uniform assessment by the multiple notified bodies has resulted in a major shakeup to
the regulation of devices in the EU. As such, at time of publication, the EU is currently transitioning
from the IVD Directive 98/79/EEC (IVDD) to the IVD Regulation EC 2017/746 and the Medical
Device Directive 93/42/EEC and the AIMD Directive 90/385/EEC to the single regulation for
medical devices, EC 2017/745 (the MDR). In the period leading up to 26 May 2025, some devices
can be legally on the market with a CE mark obtained under a directive or under a regulation. A
major difference between directives and regulations in the EU is that directives were transposed
into the law of each Member State. Transposition allows for interpretation on the intent of thedirective. As such, some aspects of the EU Directives for devices were implemented in significantly
different means by each Member State. The regulations in contrast, must be incorporated into
Member State law in their entirety. This will enable greater consistency in implementation.
Another driver for changes to EU law was the variable quality of assessment from the notified
bodies, the conformity assessment bodies for CE marking. To be designated as a notified body forthe new regulations, there is much greater scrutiny by the designation authorities, including theEuropean Commission, of the expertise and practices of these bodies. The goal is to ensure greater
quality and consistency of the pre-market assessment by notified bodies.
Both the new regulations, the IVDR and the MDR, have been implemented to ensure a stronger
emphasis on a life-cycle approach to safety, backed up by clinical data. Although the previous
directives, the MDD and the AIMD, are not significantly different compared to the new regulation—the MDR brings more stringent requirements for the designation of Notified Bodies, withincreased control and monitoring by the NRAs and the European Commission. As requirements
under the regulations regarding the qualification of Notified Body assessment staff is greatly
strengthened, there is the possibility that products assessed positively under the directives will
not be considered “good enough” with a more informed and critical opinion of subject matter
expert assessor. This enhanced oversight applies equally to the new IVDR.
Although the change from directives to regulations is an incremental change for medical devices,
it is relatively an enormous change for IVDs. Approximately 85% of IVDs are self-declared by their
manufacturer as meeting the requirements for CE marking under the IVDD. This figure will be thereverse under the IVDR, with most IVDs requiring a notified body pre-market assessment for CE
marking.
Regulatory Profile for Glucose Self-monitoring Tools 68

The diagrams below indicate the timelines for transitioning to the new regulations. The diagrams
indicate that if a device has a certificate issued by a notified body under a relevant directive, theproduct may benefit from an extended transition period, provided the certificate has not expired.
Regardless of the date of expiration, no product can be made available to the market after 26 May
2024, and, from 27 May 2025, all goods that are distributed to end users must comply with the new
regulations. However, from 26 May 2022, all devices must meet the new, enhanced, post-market
requirements of the regulations, even if they are CE marked according to the Directives. Of
interest, although many IVDs do not have certificates issued by notified bodies according to theIVDD, those for self-tests do.

Diagram 1 Transition Period for EU MDR 92

92

https://ec.europa.eu/health/sites/health/files/md_newregulations/docs/timeline_mdr_en.pdf accessed 19
Jan 2021
Regulatory Profile for Glucose Self-monitoring Tools 69

Diagram 2 Transition Period for EU IVDR 93

As per the WHO regulatory framework, the GHTF guidance, and as per the FDA and the EU
regulation of medical devices, albeit under the directives or the regulation, follows the basic
principles of adapting pre- and post-market controls according to the risks that the devices poses.
The MDD, AIMD and MDR recognise four risk classes of medical devices, from the lowest risk,
Class I, with classes IIa, IIb and finally to the highest risk group, Class III. Under the directives, ananalysis of products on the market by the European Network for Health Technology
Assessment (EUnetHTA) 94 indicate that CGMs are often regulated under the MDD and not as
active implantable medical devices under the AIMD, although it can be argued that sensors meetthe definition of active implantable devices. From 26 May 2021, they will fall under the MDR. Useof international standards is endorsed in the regulations as effective mechanisms fordemonstrating conformity.
The IVDR, in contrast, represents a major shift in identifying the risk class of IVDs. Under the IVDD,
the risk class was pre-assigned, with two lists: a high-risk list known as List A of Annex II of theIVDD, of products used in screening of the blood supply, and a lower risk group, known as List B
of Annex II of the IVDD, which includes SMBGs. All other IVDs, which according to recent analyses,
accounts for approximately 90% of IVDs, only require self-declaration for CE marking. No notified
body assessment pre-market is required to assign the CE mark. This has, as seen in the COVID-19
pandemic, been abused by often well-meaning manufacturers who have CE marked products that
do not meet the requirements.
Regardless of the need (or not) for pre-market independent assessment, all IVDs under the IVDD
must meet the basic Essential Principles of safety and performance described in Annex I of theIVDD, and any other EPs as described in this Annex. A quality system aligned with ISO 13485 will
https://ec.europa.eu/health/sites/health/files/md_newregulations/docs/timeline_ivdr_en.pdf Accessed 19
January 2021
94 Agency for Quality and Accreditation in Health Care and Social Welfare (AAZ), Main Association of Austrian Social
Security Institutions (HVB), The Norwegian Institute of Public Health (NIPHNO). Continuous glucose monitoring (CGM
real-time) and flash glucose monitoring (FGM) as personal, standalone systems in patients with diabetes mellitus treatedwith insulin. Joint Assessment.
Zagreb: EUnetHTA; 2018. Report No.: OTJA08.
93

Regulatory Profile for Glucose Self-monitoring Tools 70

meet the QMS requirements of the Directive. Certain technical documentation supporting theanalytical performance of the device, and for SMBGs, its use in the hands of self-testers, must be
kept on file and reviewed by the notified body. A notified body, when accepting an application for
an SMBG will examine the design of the device and assess the design-related requirements of thedirective. They will ensure that testing has been undertaken in the hands of lay users and issuitable and works for this testing group. They will also ensure that the information provided withthe device on its label and its instructions for use. Under the IVDD, the notified body will also
assess the impact of changes to the device on its conformity to the regulation. The CE mark is
dependent on a positive assessment of conformity of the device and its manufacturing.
Manufacturers often utilise relevant international standards to demonstrate conformity for the
IVDD.
The IVDR and MDR thus represent a giant leap in regulatory requirements for many devices,
including for those that have already undergone notified body scrutiny (i.e. those that are Class
IIa, IIb or Class III medical devices, or are List A or B under Annex II of the Directive). Although
there are many new requirements, few existing requirements have been removed.
The new regulations bring more stringent requirements for the designation of Notified Bodies,with increased control and monitoring by the national competent authorities and the European
Commission. This means that the quality of pre-market assessment is expected to be much morethorough and accountable.
For many stakeholders, a significant achievement that the regulations bring is the enhanced
traceability and effectiveness of post-market safety-related activities. This is aided by therequirements for a unique device identifier (UDI), that will track the manufacturer, the productand its manufacturing information, such as lot number. The information stored on this unique bar
code is readable with scanners that most distributors of the product will hold, as well as the
manufacturer and the regulatory agency. Of importance for devices for diabetes, this should act
as a deterrent to counterfeiting. Transparency will also be increased because of the enhancements
to the functions of the European Database for Medical Devices (Eudamed). More information on
the market authorisation of devices as well as clinical studies will be made public. Manufacturers
are responsible for entering the necessary data on Eudamed, which includes the UDI database,and for keeping it up to date. The notified body will check the veracity of the information provided.
Under the Regulations, every manufacturer must have a role within the business known as “theperson responsible for regulatory compliance, or PRRC” (Article 15 IVDR, MDR). An abbreviated listof the duties of the PRRC includes:• Check conformity of devices with QMS procedures before they are released• Make sure all Technical Documentation and Declarations of Conformity are up to date
• Ensure all post-market surveillance and reporting obligations are met
As with the current Directives, manufacturers outside the EU/EEA shall have a contract with anauthorised representative inside the EU. This role takes on legal liability for the product.
Manufacturers of some implantable devices will have to provide an implant card for the patient.
The aim of introducing an IC has been to achieve three main objectives:
1. Enable the patient to identify the implanted devices and to get access to other information
related to the implanted device (e.g., via Eudamed, and other websites).
2. Enable patients to identify themselves as persons requiring special care in relevant situations(e.g., security checks).
3. Enabling emergency clinical staff or first responders to be informed about special care/needs
for relevant patients in case of emergency situations.
It is not clear at this point if this implant cards will be a requirement for CGMs.

Regulatory Profile for Glucose Self-monitoring Tools 71

The new regulations reinforce the requirements for clinical evaluation (Article 61 of the MDR) or,in the case of IVDR, performance evaluation (Article 56 of the IVDR). The notified body oversite ofthese requirements will be stringent and therefore this represents some of the biggest changes
compared to the previous regimes. The shift in the MDR is that most implantable devices will now
need to undergo clinical investigations. Frequently, the use of published experienced gained withother equivalence devices, similar to the use of a predicate device in the US, was the major sourceof clinical evidence. This may no longer be sufficient.
For IVDs, under the IVDD it was important to demonstrate analytical performance, and for selftests, testing in the hands of lay users. Under the IVDR, these requirements expand significantly.
There must also be evidence of scientific validity, the GHTF termed adopted to indicate clinicalassociation of the marker and the disease, i.e., glucose and diabetes. There must also be clinicalevidence. Though this can be drawn from the literature, there is still the need to demonstrateperformance in the hands of self-testers.
In the EU, certain international and other consensus standards are officially recognised as
representing best practice and/or state of the art, and go through an official assessment processof harmonisation, whereby the content therein is mapped to the EU regulatory requirements.
These standards become what is known as EN standards. For the various Directives, lists ofharmonised standards are provided on the EC website 95,96,97 . EN ISO 13485, for QMS and EN ISO
14179 for Risk Management of devices, are common horizontal standards applying to both medical
device and IVD Directives. A well-known vertical standard for IVDs is EN ISO 15197:2015 In vitro
diagnostic test systems - Requirements for blood-glucose monitoring systems for self-testing inmanaging diabetes mellitus. Most manufacturers with IVDD compliant, CE marked SMBGs will have
utilised this standard to demonstrate performance in the hands of self-testers for their devices.
At the point of publication of this report, no standards have been recognised as harmonised for
the MDR or the IVDR. Manufacturers must assess whether, in light of the other sources, such as
the new FDA guidance on SMBGs, if EN ISO 15197 still represents state-of-the-art for their devices.
Any solution to demonstrate conformity must be justified.
A significant part of the whole of lifecycle approach of the new regulations is the increase inrequirements for manufacturers to ensure ongoing conformity in the post-market environment.
Post-market surveillance mechanisms must include proactive measures. With IVDs that are selftests, this is not simple. A manufacturer can include in their arrangements with distributors toreceive regular updates on complaints or other feedback given to the final vendor by thepurchasing diabetic. They can also ensure patients are encouraged to give feedback in any
instructions provided with the strips. In contrast, the latest FDA guidance on SMBG’s includes
requirements for test strip lot release criteria and sampling plans for testing to be included in a510(k) application. Regardless, despite the enhanced requirements in the EU, implementation of
pro-active measures for self-tests will prove difficult. The regulations also require increased
vigilance by regulators, enhanced follow-up by notified bodies to ensure post-market
commitments are being implemented by the manufacturer, and greater communication between
the regulators of the Member States.
Performance requirements are laid out in the Essential Requirements of the Directives and theGeneral Safety and Performance Requirements of the Regulations. These requirements are always
identified in Annex I of the laws, indicating their importance to the law. Both the directives andregulations describe the types of studies expected to be undertaken to demonstrate performance,
but the new regulation takes the evaluation of the studies one step further. A manufacturer must
demonstrate how the validated performance meets the clinical needs. To do this, study design
https://ec.europa.eu/growth/single-market/european-standards/harmonised-standards/implantable-medicaldevices_en Accessed 19 January 2021
96
https://ec.europa.eu/growth/single-market/european-standards/harmonised-standards/iv-diagnostic-medicaldevices_en Accessed 19 January 2021
97
https://ec.europa.eu/growth/single-market/european-standards/harmonised-standards/medical-devices_en
Accessed 19 January 2021
95

Regulatory Profile for Glucose Self-monitoring Tools 72

must include an assessment of how any acceptance criteria will lead to a clinically relevant result.
The manufacturer must also justify why the results of the studies scientifically demonstrate thatthe intended clinical benefit or benefits and safety will be achieved, according to state-of-the-art
in medicine. As such, greater justification for a test’s performance is required. The enhanced postmarket surveillance requirements are in place to ensure that the performance remains constantand is state of the art. Products without such evidence will lose their CE mark when re-assessed
during ongoing surveillance audits by the notified bodies. These audits, scheduled annually,
include at least one announced audit.

10.2. Regulation of Self-Monitoring Blood Glucose Test Systems (SMBGs) in

the EUThe table below compares regulation of SMBGs under the IVDD and IVDR. For the EU
regulations, the individual components of a system are considered separately. However, theperformance evaluation made by the manufacturer, which is reviewed during notified bodyassessment of the strips, will include information on the performance of the glucose meter.
EU Product Regulation Overview_SMBGs
Self-Monitoring
Blood
Glucosesystems: Glucose StripClassification
Conformity assessment with a notified
body?
Conformity assessment route

IVDD

IVDR

Annex II List B
YesClass C (Annex VIII 2.3 Rule 3k98)
Yes

Annex IV (full quality assurance) OR
Annex V (EC type-examination) WITH:
Annex VI (EC verification) OR Annex
VII (production quality assurance).

Notifiedbody
auditingofmanufacturer’s quality management
systemPost market requirements

Risk based approach over 5 year
certification cycle. No mandatory
requirements.
Reactive post market surveillance

Annex IX Conformity assessment
based on QMS and assessment oftechnical documentation, OR
Annex X Conformity assessment basedon type Examination WITH Annex XI
Conformity assessment based on
production quality assurance
Annual review over the 5 year
certification cycle including one
unannounced on-site audit.
Reactive and pro-active post market
surveillance,
Submission of a yearly Post market
surveillance update report to thenotified body.

The assessment of a SMBG by a notified body under the IVDD includes an assessment of thedesign, manufacture and performances of the system. This will include aspects affecting its
suitability for non-professional users. As the UK was until 1 January 2021 an EU Member State, the
MHRA published relevant guidance for the assessment of self-tests by a notified body 99. Thisclarified requirements to ensure that test reports provide sufficient data to support all
performance claims. The guidance also highlighted the necessity to ensure that sample type notedin the labelling had been validated, as had acceptable usage ranges for environmental factors suchas temperature and humidity; that the product was robust with respect to mechanical resistance;that the product had been subjected and proved safe with respect to aspects such as electricaland mechanical hazards; and that any associated software had been appropriately validated. The
guidance also proposed that lay user studies would be performed for all self-test devices unlesssimilarity to previous devices renders this unnecessary. If not included, the notified body should
Devices are Class C if they are intended (k) for management of patients suffering from a life-threatening disease orcondition.
99Competent Authority (UK) Medicines and Healthcare products Regulatory Agency July 2012 “Guidance for notified bodies
on the regulation of IVDs for self-testing” https://www.fdanews.com/ext/resources/files/archives/0/07/07-16-12IVD.pdf Sourced 31 January 2021
98

Regulatory Profile for Glucose Self-monitoring Tools 73

critically assess the documented rationale for this decision. The guidance also stressed theimportance of how and what information was included in the instructions for use. Although thisguidance was created to support the assessment of all self-testing devices, it drew heavily on therequirements as described in the harmonised version of ISO 15197 In vitro diagnostic test systems- Requirements for blood-glucose monitoring systems for self-testing in managing diabetes mellitus.
Thus, ISO standard 15197 forms a cornerstone of state of the art for compliance with EU
requirements for SMBGs.
Under the IVDR, an application for a self-test must not be bundled with other IVDs, as is possible
for Class C and B IVDs that are not for self-testing. A subject matter expert will assess the clinicaland analytical performance of the system, another will assess the technology. Finally, a clinicalopinion will be provided. Manufacturers of Class C IVDs must annually update the performance
evaluation report that they have initially submitted to their notified body. The update must reflect
the findings of the performance and safety of the device post-market, using both reactive andproactive surveillance methods. In addition, on an annual basis, the manufacturer must prepare aperiodic safety update report, again, reflecting the findings of the post market surveillance
relevant to the device. Thus, along with the potential for an unannounced audit, there will be aneed for a manufacturer to be seriously monitoring the ongoing compliance of their SMBG.

10.3. Regulation of Continuous Glucose Monitoring Systems (CGMs) in the EU
Under the MDD, most sensors were classified as Class IIb. Under the new MDR, the following
aspects may apply to CGMs. Classification rules for the MDR take into account a number of factors,
including duration. If a sensor is in place for between 60 minutes and 30 days, the duration isconsidered short-term, any longer and it is considered long-term. Sensors that are placed
subcutaneously are considered surgically invasive (MDR Annex VIII Rule 2.2). They are also
considered active devices intended for diagnosis and monitoring (MDR Annex VIII Rule 2.4).
Depending on their features, CGMs may fall into several classes, ranging from Class IIa to Class III,
if they are associated with the delivery of insulin. Clinical trials are expected to be performed forClass III medical devices and for implantable devices in the EU. The risk class in the EU under the
MDR does not impact on the depth of assessment of a medical device by a notified body. For lowrisk medical devices, a manufacturer is able to apply for technical documentation assessment of agroup of related devices. The lower the risk class, the bigger the grouping is possible. The notified
body chooses one product on a representative basis to undertake an initial in-depth technical andclinical assessment, and the other technical files are then relegated for assessment during thecertification five-year cycle. The requirements for both active and reactive post-market
monitoring that apply to SMBGs also apply to CGMs. No specific harmonised EN standards areavailable in support of performance of CGMs, however, an ISO series ISO/IEEE 11073 provides
guidance for interoperability and related aspects for communication functionality of CGM devices.

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