Medical Device Regulatory Challenges: Global Market Access

applied
sciences
Review
Global Regulatory Challenges for Medical Devices: Impact on
Innovation and Market Access
Carolina Amaral 1 , Maria Paiva 1 , Ana Rita Rodrigues 1 , Francisco Veiga 2,3 and Victoria Bell 1,3, *
1
2
3
*
Citation: Amaral, C.; Paiva, M.;
Rodrigues, A.R.; Veiga, F.; Bell, V.
Global Regulatory Challenges for
Medical Devices: Impact on
Innovation and Market Access. Appl.
Social Pharmacy and Public Health Laboratory, Faculty of Pharmacy, University of Coimbra,
3000-548 Coimbra, Portugal; [email protected] (C.A.); [email protected] (M.P.);
[email protected] (A.R.R.)
Drug Development and Technology Laboratory, Faculty of Pharmacy, University of Coimbra,
3000-548 Coimbra, Portugal; [email protected]
LAQV-REQUIMTE, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra,
3000-548 Coimbra, Portugal
Correspondence: [email protected]
Abstract: Medical devices play a crucial role in human health. These are instruments, machines or
even software programs used to diagnose, treat, monitor or prevent health conditions. They are
designed to help improve patients’ quality of life and range from simple items, such as thermometers,
to more advanced technologies, such as pacemakers. In order to guarantee the safety and efficacy of
medical devices intended for use on patients, the establishment of appropriate regulatory frameworks
is crucial to ascertain whether devices function as intended, comply with safety standards and
offer benefits that outweigh the associated risks. Depending on the country, different regulatory
agencies are responsible for the evaluation of these products. The regulatory landscape for medical
devices varies significantly across major markets, including the European Union, the United States
of America and Japan, reflecting diverse approaches aimed at ensuring the safety and efficacy of
medical technologies. However, these regulatory differences can contribute to a “medical device
lag,” where disparities in approval processes and market entry timelines driven by strict regulatory
requirements, increasing device complexity and the lack of global harmonization, result in delays
in accessing innovative technologies. These delays impact patient access to cutting-edge medical
devices and competitiveness in the market. This review aims to address the regulatory framework of
medical devices and the approval requirements by the European Commission (EC), the Food and
Drug Administration (FDA) and Pharmaceuticals and Medical Device Agency (PMDA).
Keywords: medical device; regulatory framework; European Union; United States of America; Japan
Sci. 2024, 14, 9304. https://doi.org/
10.3390/app14209304
Academic Editor: Piotr Gas
1. Introduction
Received: 14 September 2024
In recent years, medical devices have played a crucial role in revolutionizing medicine
and improving patient care. They include a broad range of products, such as instruments,
apparatuses, equipment and materials used for the diagnosis, prevention, monitoring
and treatment of health conditions. Unlike medicines, medical devices act physically or
mechanically on the body without chemical interference [1].
The development of medical devices is a complex process that involves several stages,
from the initial research and design phase to regulatory validations [2–4]. The introduction
of medical devices in the market is governed by stringent regulatory frameworks that
ensure the products meet safety, efficacy and quality standards. However, the regulatory
landscape of medical devices varies significantly across different regions. In this review
article, the European Union (EU), the United States of America (USA) and Japan will be the
focus, given the global importance of these regions in the medical devices sector. These
three markets not only represent some of the largest economies in the world, but they
also have advanced regulatory systems that directly influence the practices adopted by
Revised: 9 October 2024
Accepted: 10 October 2024
Published: 12 October 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Appl. Sci. 2024, 14, 9304. https://doi.org/10.3390/app14209304
https://www.mdpi.com/journal/applsci
Appl. Sci. 2024, 14, 9304
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other countries, particularly in aspects such as definition and classification, nomenclature,
approval procedures and post-market requirements. Differences in such aspects pose
both challenges and opportunities for global harmonization, an effort actively pursued by
initiatives such as the Global Harmonization Task Force (GHTF) [5] and the International
Medical Device Regulators Forum (IMDRF) [6]. Understanding the regulatory frameworks
in these major markets is crucial for comprehending the broader dynamics of medical
device approval and post-market surveillance, and their associated impacts on innovation
and patient care [7–10].
In the EU, stringent regulations, exemplified by the Medical Device Regulation (MDR),
mandate comprehensive pre-market assessments and robust post-market surveillance
to ensure patient safety [11]. The Food and Drug Administration (FDA), in the USA,
implements a similarly rigorous approval process with distinct protocols for pre-market
and post-market phases. These protocols include extensive clinical trials and the continuous
monitoring of device performance after market entry [12]. Japan, while a significant player
in the global medical device market, faces unique regulatory challenges. The requirements
for domestic clinical data and a complex reimbursement system complicate the approval
process, leading to notable delays, commonly referred to as “medical devices lag” [13–15].
Medical devices lag, characterized by delays in the approval and adoption of new medical
devices, arises from stringent regulations, increasing device complexity and challenges
in achieving global harmonization [16,17]. The consequences of this are multifaceted,
impacting patient access to innovative treatments and affecting market competitiveness.
However, various mitigation strategies, including regulatory reforms and harmonization
efforts, are being implemented to address these issues [18,19].
This review article aims to clarify the concept of medical devices, detailing their
development process and evaluating the current market landscape for these products. In
addition, it will explore the regulatory frameworks in major markets such as the EU, the
USA and Japan, offering a comprehensive comparison of their regulations. In this context,
a concern known as “medical device lag” will also be addressed, focusing on its causes,
consequences and how delays in regulatory approval can impact both innovation and
patient care. Finally, this article will discuss current initiatives aimed at promoting global
regulatory harmonization for medical devices.
2. Methods
To frame this article, a review of the literature was conducted. To identify relevant
information, we used the following databases: PubMed/Medline, Research Gate and
Science Direct. The search terms incorporated both keywords and controlled vocabulary
for the databases used. Some examples of the search terms used included “medical devices
regulatory framework”, “medical devices regulation in EU”, “medical devices regulation
in US” and “medical devices regulation in Japan”. The search was restricted to the English
language and included publications from 2010 to 2024. This timeframe allowed us to
understand significant developments in the regulatory standards and guidelines over the
last decade, while ensuring the inclusion of the most recent and relevant information
regarding the regulation of medical devices.
All regulation documents regarding the approval of medical devices were obtained
from the websites of the respective authorities: EMA, FDA and PMDA. Intergovernmental
organizations such as the World Health Organization (WHO) and institutions such as the
European Commission (EC) were also analyzed to include regulatory guidelines and laws.
Initially, 234 related articles were found. A preliminary review was conducted, where
the most relevant articles were considered for the present article. In addition, given the
significant changes in European medical device legislation with the introduction of the MDR
in 2017, we excluded all the articles discussing European legislation that were published
before this date, to ensure that the review would reflect the current regulatory environment
and avoid outdated information. After carrying out this process, we obtained 37 articles,
which were evaluated and included for their significant contribution to understanding the
Appl. Sci. 2024, 14, x FOR PEER REVIEW
Appl. Sci. 2024, 14, 9304
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MDR in 2017, we excluded all the articles discussing European legislation that were pub3 ofen24
lished before this date, to ensure that the review would reflect the current regulatory
vironment and avoid outdated information. After carrying out this process, we obtained
37 articles, which were evaluated and included for their significant contribution to underregulatory
frameworks
medical devices
in the
EU, US
Japan.
1 provides
standing the
regulatory of
frameworks
of medical
devices
inand
the EU,
US Figure
and Japan.
Figure a1
flowchart
of
the
selection
of
the
reviewed
articles.
provides a flowchart of the selection of the reviewed articles.
Figure 1.
1. Flowchart
Flowchart of
of the
the selection
selection of
of the
the reviewed
reviewed articles.
articles.
Figure
3.
3. Overview
Overview of
of Medical
Medical Devices
Devices
3.1.
Definition
3.1. Definition
According
apparatus, implement,
implement,
According to
to the
the WHO,
WHO, aa medical
medical device
device is
is “any
“any instrument,
instrument, apparatus,
machine,
appliance,
implant,
reagent
for
in
vitro
use,
software,
material
or
other
machine, appliance, implant, reagent for in vitro use, software, material or other similar
similar
or related article, intended by the manufacturer to be used, alone or in combination for
or related article, intended by the manufacturer to be used, alone or in combination for a
a medical purpose” [1]. From this comprehensive definition, it is possible to realize that
medical purpose” [1]. From this comprehensive definition, it is possible to realize that
medical devices encompass a wide range of essential products in the field of medicine and
medical devices encompass a wide range of essential products in the field of medicine and
human health.
human health.
These products can be used by healthcare professionals and non-healthcare professionThese products can be used by healthcare professionals and non-healthcare profesals (e.g., patients, relatives, etc.) for various purposes, including diagnosing, preventing,
sionals (e.g., patients, relatives, etc.) for various purposes, including diagnosing, preventmonitoring, treating or alleviating diseases; investigation, monitoring, treating, alleviating
ing, monitoring, treating or alleviating diseases; investigation, monitoring, treating, alleor compensating for injuries; investigating, replacing, modifying or supporting anatomy or
viating or compensating for injuries; investigating, replacing, modifying or supporting
physiological processes; supporting or sustaining life; controlling conception; disinfecting
anatomy or physiological processes; supporting or sustaining life; controlling conception;
medical devices; and providing information through the in vitro examination of specimens
disinfecting medical devices; and providing information through the in vitro examination
derived from the human body [20,21]. Figure 2 shows some examples of medical devices
Appl. Sci. 2024, 14, x FOR PEER REVIEW
4 of 25
of specimens
derived
from the
human body [20,21]. Figure 2 shows some examples of
according
to their
respective
purpose.
medical devices according to their respective purpose.
Given the vast variety of medical devices available, it is essential to establish a system
to classify these products. Such a system should ensure that products entering the market
are clearly identified as medical devices and that they meet the necessary quality and
safety standards. This will guarantee that each device can fulfill its intended functions
while adhering to the regulatory standards specific to each market [10,22].
Figure2.2.Medical
Medicaldevice
deviceexamples
examplesaccording
accordingtototheir
theirrespective
respectivepurpose.
purpose.
Figure
The classification of medical devices can be somewhat challenging, given that, depending on its intended purpose, the product may or may not be considered a medical
device. Vaseline® is a good example of this. If it is used as an emollient for healthy skin, it
is considered a cosmetic and body care product; if it is used as a laxative, it is considered
Appl. Sci. 2024, 14, 9304
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Given the vast variety of medical devices available, it is essential to establish a system
to classify these products. Such a system should ensure that products entering the market
are clearly identified as medical devices and that they meet the necessary quality and safety
Figure 2. Medical device examples according to their respective purpose.
standards. This will guarantee that each device can fulfill its intended functions while
adhering to the regulatory standards specific to each market [10,22].
The classification of medical devices can be somewhat challenging, given that, deThe classification of medical devices can be somewhat challenging, given that, depending on its intended purpose, the product may or may not be considered a medical
pending on its intended purpose, the product may or may not be considered a medical
device. Vaseline® is
a good example of this. If it is used as an emollient for healthy skin, it
device. Vaseline® is a good example of this. If it is used as an emollient for healthy skin, it
is considered a cosmetic and body care product; if it is used as a laxative, it is considered
is considered a cosmetic and body care product; if it is used as a laxative, it is considered
a medicine; and if it is used as a lubricant during medical procedures, it is considered a
a medicine; and if it is used as a lubricant during medical procedures, it is considered a
medical device [15]. Additionally, products that might be considered medical devices in
medical device [15]. Additionally, products that might be considered medical devices in
some jurisdictions but not in others include disinfection substances, aids for persons with
some jurisdictions but not in others include disinfection substances, aids for persons with
disabilities, devices incorporating animal and/or human tissues and devices for in vitro
disabilities, devices incorporating animal and/or human tissues and devices for in vitro
fertilization or assisted reproduction technology [20,21].
fertilization or assisted reproduction technology [20,21].
3.2.
Development
Process
3.2.
Development
Process
The
development
and
manufacture
ofof
medical
devices
is is
a complex
and
demanding
The development
and
manufacture
medical
devices
a complex
and
demanding
process
that
requires
precise
specifications
and
high-quality
standards
toto
ensure
that
the
process
that
requires
precise
specifications
and
high-quality
standards
ensure
that
the
final
product
complies
with
stringent
legal
regulations.
Furthermore,
this
process
must
bebe
final
product
complies
with
stringent
legal
regulations.
Furthermore,
this
process
must
meticulously
facilitate reproducibility.
reproducibility.Several
Severalstages
stages
meticulouslydocumented
documentedtotouphold
upholdquality
quality and
and facilitate
are
are
included
in
this
process,
as
shown
in
Figure
3,
that
guide
the
transition
from
a
concepincluded in this process, as shown in Figure 3, that guide the transition from a conceptual
tual
design
a fully
functional
product
ready
in the
medical
industry
[2,3].
design
to atofully
functional
product
ready
forfor
useuse
in the
medical
industry
[2,3].
Figure 3. Stages in the development and manufacture of a medical device [23].
Figure 3. Stages in the development and manufacture of a medical device [23].
The first stage of medical device development is critical, as it sets the foundation for
the entire process. In this stage, the focus is on analyzing the potential opportunities and
risks. Initially, it is necessary to identify a medical need or innovation opportunity. Then, it
is important to clearly define the intended use of the device to be developed, identify similar
products on the market and assess consumer demand and the factors that differentiate the
new product. In addition, it is essential to gather users’ needs to direct the design process.
At the same time, an initial risk analysis is carried out to understand potential technical and
clinical problems that may arise during the rest of the device development process [23,24].
During stage 2, a financial viability analysis is conducted to assess the required
investment and potential profit the device can generate. In addition, a formal risk analysis
is carried out and the regulatory requirements applicable to the product to be developed
are identified. The first prototype is built and serves as proof of concept to demonstrate
the practical functionality of the device. This prototype undergoes preliminary safety and
effectiveness tests to identify any technical issues and make necessary adjustments to the
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design. These tests help refine the product concept, which is then detailed, including its
functionalities, critical components and the materials required for production [23,24].
The third stage places significant emphasis on creating the design of the device at a
more detailed level. The design of the prototype created in the previous phase is rigorously
evaluated and validated to ensure that the device fulfils the intended functionality under
various conditions and, above all, that it meets the user’s needs. In addition, the design is
verified and the prototype is constantly developed and improved to ensure it complies with
all relevant regulatory requirements. This stage is critical to guarantee that the product is
ready for the next phases of manufacturing and clinical trials [23,24].
In the fourth stage, a final validation of the product is performed. Depending on the
class of the device, clinical trials are required to confirm its safety and efficacy in real-world
use. It is important to mention that these tests follow strict standards of Good Clinical
Practices (GCP). During this period, clinical data is collected and submitted to regulatory
agencies that review and analyze the results and, if they are satisfactory, grant approval so
that the device can be placed on the market [23].
In the last phase of a medical device’s development, phase 5, after regulatory approval
has been obtained and the device has been launched commercially, it is crucial to monitor
its performance post-market. This involves collecting feedback from users and ensuring
that any problems or faults are resolved quickly. Activities such as post-market surveillance,
safety reports and continuous improvements in design and manufacture are carried out to
keep the device safe and effective [23,24].
The development process of a medical device can take more or less time, depending on
factors such as the complexity of the device and the regulatory requirements. However, this
process usually takes longer than a year. The costs inherent in developing a medical device
can vary depending on the level of innovation involved and the development timeline, for
example and can range from hundreds of thousands to several million dollars [23].
3.3. Medical Devices Market
The global medical device market is primarily driven by increased investment in
the sector and favorable regulatory environments for device approval and testing [25].
Regional support for device demand, along with the gradual recovery of the global economy
from the pandemic, have also contributed to market growth. Wearable medical devices
are gaining popularity among consumers, further increasing market expansion. Key
factors, such as advanced product models, innovative features, competitive pricing and
intensified marketing efforts by market leaders are expected to expand market growth in
the future [25,26].
Consumer lifestyles, an increase in chronic diseases and fewer clinic visits for regular checkups are expanding the market for home monitoring medical devices. Patients
are looking for more convenient ways to manage their health, increasing the demand for
devices that allow remote monitoring and early detection of health issues [27–29]. Additionally, the prevalence of chronic diseases such as hypertension, diabetes and cardiovascular
disorders increases the demand for medical devices. Population reliance on ophthalmic
and orthopedic devices due to vision and mobility issues also creates new growth opportunities. Increased healthcare facilities and awareness initiatives can also help market
growth. However, the high initial costs of medical devices may pose a challenge to market
expansion [30,31].
The USA is currently the largest medical device market globally, followed by the
EU, with Japan ranking fourth [32]. The Japanese market is poised for further expansion,
particularly with the aging population projected to increase from 28% in 2020 to 38% by
2065 [33]. Additionally, North America is expected to lead the global medical device market
in terms of revenue until 2026, holding approximately 35% of the market share. This
dominance is driven by factors such as the presence of key players, expanding healthcare
infrastructure, rapid adoption of advanced medical technologies and a favorable regulatory
framework. Meanwhile, in 2026, Europe is forecasted to experience the highest compound
Appl. Sci. 2024, 14, 9304
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annual growth rate, supported by its well-established healthcare system and increasing
adoption of advanced diagnostic and treatment devices [26].
As the medical devices market expands, two segments have emerged as particularly
noteworthy due to the advances they represent in the healthcare field. These segments are
referred to as wearable technology and prosthetic innovation. The wearable technology
segment initially included simple equipment such as fitness trackers. However, to meet
the increasing demand for preventive health solutions and through the incorporation of
advanced technologies like artificial intelligence (AI) and big data, more sophisticated
devices are now available, such as continuous glucose monitors that provide real-time
data for diabetes management. These new devices enable remote patient monitoring
and improve the management of chronic diseases. On the other hand, the prosthetics
innovation segment emphasizes the development of highly personalized medical devices,
taking advantage of advances in materials science, biomechanics and robotics to produce
realistic artificial limbs. An example of a device included in this segment is the 3D-printed
prosthesis, which offers personalized adjustments for individual patients [30,31]. Both
segments not only exemplify the rapid growth of the medical devices sector, but also
emphasize the unique challenges and opportunities they present in meeting the diverse
needs of patients.
4. Regulatory Frameworks of Major Markets for Medical Devices
4.1. European Union
With the emergence of medical devices, a regulatory framework has been established
to ensure the safety and efficacy of these products’ availability within the Member States.
In the EU, the regulation of medical devices is governed by the Regulation (EU) 2017/745
of the European Parliament and of the Council of 5 April 2017, that came into force on 26
May 2021 and lays down strict rules on the safety, traceability and compliance of medical
devices in Europe [11]. This regulation repeals the Directive 93/42/EEC on medical devices
and the Directive 90/385/EEC on active implantable medical devices [11].
The main bodies involved in regulating medical devices in Europe are the EC, the
competent national authorities, and the Notified Bodies (NBs). The EC plays a crucial role
in creating and overseeing the regulations and policies of the EU. It defines the standards
that must be followed by medical device manufacturers and works with national authorities
and NBs to ensure compliance. The national competent authorities are in turn responsible
for overseeing the application of the regulations, ensuring that medical devices comply
with the regulations in their respective countries. In addition, these authorities are also
responsible for market surveillance, investigating incidents related to medical devices
and taking appropriate action. Finally, NBs are independent organizations designated by
EU member states to carry out conformity assessments of medical devices. They certify
that the devices meet the requirements of European regulations before the devices can
receive the Conformité Européenne (CE) marker, which is required to market the device in
Europe [34–36].
In addition to these organizations, the European Medicines Agency (EMA) also plays
a role in regulating medical devices. The EMA is a decentralized EU agency responsible
for the scientific evaluation, supervision and safety monitoring of medicines developed by
pharmaceutical companies for use in the EU [34]. Although the EMA is primarily focused
on medicines, it also plays a role in regulating medical devices that are combined with
medicines or considered high-risk [37].
4.1.1. Definition and Classification
According to Article 2 of Regulation (EU) 2017/745, the term “medical device” refers
to ‘’any instrument, apparatus, appliance, software, implant, reagent, material or other
article intended by the manufacturer to be used, alone or in combination, for human beings
for one or more of the following specific medical purposes: —diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, —diagnosis, monitoring,
Appl. Sci. 2024, 14, 9304
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treatment, alleviation of, or compensation for, an injury or disability, —investigation, replacement or modification of the anatomy or of a physiological or pathological process or
state, —providing information by means of in vitro examination of specimens derived from
the human body, including organ, blood and tissue donations and which does not achieve
its principal intended action by pharmacological, immunological or metabolic means, in or
on the human body, but which may be assisted in its function by such means. The following
products shall also be deemed to be medical devices: —devices for the control or support
of conception; —products specifically intended for the cleaning, disinfection or sterilization
of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this
point.” [11].
In the EU, medical devices are classified into several classes, such as class I (Isp, Imf
and Irs), class II (IIa, IIb) and class III, according to their intended purpose and intrinsic
risks [11,22]. Class I devices are considered low risk and non-invasive, and are admitted
as everyday devices or appliances. In this category, we can also consider the Class Isp
that includes sterile medical devices, the Class Imf that includes devices with a measuring
function and the Class Irs that includes reusable surgical instruments. Class II devices are
classified as Class IIa when they are considered low to medium risk and refer mainly to
devices installed within the body for a short term, or as Class IIb when they are slightly
more complex than class IIa devices. Class IIb devices are generally medium to high
risk and often include devices installed within the body for longer periods. Lastly, Class
III devices are strictly high-risk devices and for this reason, they follow a more rigorous
process for market introduction [38].
4.1.2. Market Authorization
In order to be marketed in the EU, medical devices must undergo a marketing authorization process to ensure that the devices meet stringent EU requirements, ensuring that
they meet the safety, efficacy and quality standards set by the relevant regulations before
they can be made available to consumers [39,40].
The review and authorization of medical devices is carried out by designated NBs that
ensure compliance with Regulation (EU) 2017/745. This process requires manufacturers to
prepare and submit a dossier containing specific information, such as the device’s general
description, technical specifications, risk management documentation, pre-clinical and
clinical tests results, labelling and a post-marketing surveillance plan [40].
CE Marking
The CE marking is a mandatory requirement for selling medical devices within the
Economic European Area (EEA). It plays a crucial role by certifying that these products
meet all relevant EU regulations and directives and allows the free movement of products
within the EEA. For manufacturers, obtaining the CE mark is a crucial legal requirement
for entering the European market. For consumers, it means that the product has undergone
rigorous conformity assessments, ensuring its safety and compliance with European standards [29,30]. Marking medical devices with the CE symbol follows the general principles
outlined in Article 30 of Regulation (EC) No 765/2008 and must be visibly, legibly and
indelibly applied to the device or its sterile packaging [41–43].
The NBs are the entities responsible for authorizing the application of the CE marking,
issuing conformity certificates and making decisions regarding their renewal or withdrawal [22,34]. They ensure that manufacturers comply with their obligations, cooperate
with national authorities and collaborate with other NBs across EU member states. If applicable, the CE marking must be followed by the identification number of the NB responsible
for conformity assessment procedures [35].
Obtaining a CE mark involves several key steps, from identifying the applicable
regulations for the product to affixing the CE marking, as shown in Figure 4. During this
process, the manufacturer must follow a rigorous conformity assessment procedure to
ensure compliance with these regulations.
Appl. Sci. 2024, 14, 9304
plicable, the CE marking must be followed by the identification number of the NB responsible for conformity assessment procedures [35].
Obtaining a CE mark involves several key steps, from identifying the applicable regulations for the product to affixing the CE marking, as shown in Figure 4. During this
8 of 24
process, the manufacturer must follow a rigorous conformity assessment procedure
to
ensure compliance with these regulations.
Figure4.4.Awarding
AwardingaaCE
CEmarking
markingtotoaaMedical
MedicalDevice
Device[43,44].
[43,44].
Figure
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first procedure is the Quality Management System (QMS) and technical documendevices
tation.The
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where
the
NB
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of
the
device
to
ensure
it
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requirements
in the MDR.
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rigorous
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and testing
of
amination,
wherespecified
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a representative
sample
of the
device to ensure
it meets
the
device’s
design
to
confirm
it
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the
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safety
and
performance
the essential requirements specified in the MDR. This involves rigorous evaluation and
standards.
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procedure
is commonly
for devices
more complex
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profiles.
testing of the
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to confirmused
it complies
withwith
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perThen,
there
is
the
Product
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Verification
composed
of
two
procedures:
product
formance standards. This procedure is commonly used for devices with more complex
quality
assurance
product
In the first
one, NBscomposed
evaluate the
manufacrisk profiles.
Then,and
there
is the verification.
Product Conformity
Verification
of two
proceturer’s production processes to ensure consistent compliance with the regulation. This
dures: product quality assurance and product verification. In the first one, NBs evaluate
includes ongoing surveillance and audits of the QMS to maintain adherence to regulatory
standards over time. In the second one, NBs inspect and test individual batches of devices
to confirm that the manufactured products are consistent with technical documentation and
comply with regulatory requirements. This is often used when batch-by-batch verification
is necessary due to the device’s nature or risk [45,46].
For Class I devices, manufacturers are only required to present technical documentation before affixing the CE marking. For Class Isp, Ims and Irs devices, the process
involves limited intervention from a NB for the assessment procedure. Manufacturers have
the option to submit the technical documentation with product quality assurance or with
limited QMS. Moderate-risk devices, like Class IIa and IIb devices, must undergo one of the
conformity assessment procedures involving a NB. This is crucial to ensure these devices
meet the EU’s stringent regulatory requirements. For Class IIa devices, manufacturers
can choose from the present technical documentation with full QMS, with product quality
assurance or with product verification. For Class IIb devices, the available routes are to
present the Technical Documentation with full QMS, or to perform an EC-Type Examination with product quality assurance or product verification. Finally, for Class III Devices,
characterized as high-risk, manufacturers must opt for conformity assessment procedures
that involve a NB. They can choose to present the technical documentation with full QMS,
or to perform an EC-Type Examination with product quality assurance or with product
verification if they opt not to follow the first procedure [45,47].
Appl. Sci. 2024, 14, 9304
9 of 24
After the most suitable procedure has been chosen, the product is rigorously assessed
to ensure that it fulfils the essential requirements. This can involve internal assessments
and external tests carried out by accredited laboratories or both, taking into account
the conformity assessment route chosen previously. All the data obtained through this
assessment, as well as the processes, design choices and test results that demonstrate the
product’s compliance with the essential requirements must be compiled in a technical
dossier. Finally, the Declaration of Conformity (DoC) is drafted and signed and the CE
symbol can be applied to the product and on its packaging. This means that the product is
ready to be introduced and commercialized on the European market [45,47].
Unique Device Identification
The Unique Device Identification (UDI) system is a standardized identification mechanism designed to enhance the traceability and monitoring of medical devices within the EU.
Introduced under Regulation (EU) 2017/745, the UDI system aims to improve patient safety
and simplify the management of medical devices throughout their lifecycle. It represents a
comprehensive approach to enhancing the traceability, safety and regulatory compliance
of medical devices within the EU, aligning with international standards and promoting
efficient healthcare management [11].
The UDI must be placed on the device label or on its packaging, ensuring it is visible
and easily identifiable. It is an alphanumeric code that includes standardized information,
enabling the unique identification of each medical device in the market. It consists of
two parts: the UDI Device Identifier (UDI-DI) and the UDI Production Identifier (UDIPI). The UDI-DI includes details about the manufacturer and the device model, which
remain consistent across all devices of the same model. When multiple individual units
of a medical device are packed together in a larger box or container, each higher level
of packaging must possess its own UDI-DI, except for shipping containers, which are
exempt from this requirement [48,49]. The UDI-PI contains information specific to each
unit of device production, such as the serial number, batch number, manufacturing and/or
Appl. Sci. 2024, 14, x FOR PEER REVIEW
10 of
25
expiration date and software identifier. This part of the code varies for each individual
unit
produced [49]. Figure 5 provides an example of an UDI in the EU.
Figure
Figure 5.
5. EU
EU UDI
UDI example
example [49].
[49].
European Database
Database on
on Medical
Medical Devices
Devices
European
The European
European Database
Database on
on Medical
Medical Devices
Devices (EUDAMED)
(EUDAMED) isis aa comprehensive
comprehensiveelecelecThe
tronic system
system established
established and
and managed
managed by
by the
theEC.
EC.ItItwas
wascreated
createdtotoenhance
enhancetransparency,
transparency,
tronic
traceability and
and coordination
coordination in
in the
the regulation
regulation of
of medical
traceability
medical devices
devices across
across the
the EU
EU [48,50].
[48,50].
EUDAMED
was
designed
to
provide
public
access
to
comprehensive
information
on
EUDAMED was designed to provide public access to comprehensive information on
all
medical
devices
available
in
the
EU
market.
This
includes
details
on
certificates
issued
by
all medical devices available in the EU market. This includes details on certificates issued
NBs
and
information
concerning
relevant
economic
operators.
The
database
facilitates
the
by NBs and information concerning relevant economic operators. The database facilitates
unique
identification
andand
traceability
of devices
within
the internal
market.
Furthermore,
the
unique
identification
traceability
of devices
within
the internal
market.
FurtherEUDAMED
informs
the public
investigations
and assists
in meeting
more,
EUDAMED
informs
the about
publicclinical
about clinical
investigations
andsponsors
assists sponsors
in
regulatory
requirements.
It
also
aids
manufacturers
in
fulfilling
their
obligations
regarding
meeting regulatory requirements. It also aids manufacturers in fulfilling their obligations
regarding reporting on serious incidents and field safety corrective actions. Overall, EUDAMED supports competent authorities in EU Member States and the EC by facilitating
regulatory tasks and fostering cooperation among them [43,50,51].
EUDAMED consists of several interconnected electronic systems, as shown in Figure
6, including actor registration, which allows economic operators to submit the infor-
Appl. Sci. 2024, 14, 9304
EUDAMED was designed to provide public access to comprehensive information on
all medical devices available in the EU market. This includes details on certificates issued
by NBs and information concerning relevant economic operators. The database facilitates
the unique identification and traceability of devices within the internal market. Furthermore, EUDAMED informs the public about clinical investigations and assists sponsors in
10 of 24
meeting regulatory requirements. It also aids manufacturers in fulfilling their obligations
regarding reporting on serious incidents and field safety corrective actions. Overall, EUDAMED
competent
authorities
EU Member
States
and the
EC byEUDAMED
facilitating
reportingsupports
on serious
incidents
and fieldin
safety
corrective
actions.
Overall,
regulatory
tasks
and
fostering
cooperation
among
them
[43,50,51].
supports competent authorities in EU Member States and the EC by facilitating regulatory
consists
of several
interconnected
electronic systems, as shown in Figure
tasksEUDAMED
and fostering
cooperation
among
them [43,50,51].
6, including
actor
registration,
which
allows
economic
operators
theFigure
infor-6,
EUDAMED consists of several interconnected electronic
systems,toassubmit
shown in
mation
necessary
to
obtain
an
actor
identifier
or
a
single
registration
number.
UDI/Device
including actor registration, which allows economic operators to submit the information
registration
used an
foractor
registering
medical
devices.
Notified
BodiesUDI/Device
and Certificates
is
necessary toisobtain
identifier
or a single
registration
number.
registrawhere
NBs
should
register
any
information
regarding
the
certificates
issued.
Clinical
intion is used for registering medical devices. Notified Bodies and Certificates is where NBs
vestigations
andany
performance
studies
are used
for managing
information
clinical inshould register
information
regarding
the certificates
issued.
Clinical on
investigations
vestigations.
Vigilance
and
post-market
surveillance
monitors
adverse
events
and other
and performance studies are used for managing information on clinical investigations.
safety
issues
and
lastly,
market
surveillance
oversees
market
compliance
and
enforcement
Vigilance and post-market surveillance monitors adverse events and other safety issues
actions
[51].market surveillance oversees market compliance and enforcement actions [51].
and lastly,
Figure6.6.Modules
Modulesof
ofEUDAMED
EUDAMED[51].
[51].
Figure
4.1.3. Post-Market Surveillance
Article 83 of Regulation (EU) 2017/745 outlines the requirements for the post-market
surveillance system [11]. Manufacturers must establish and maintain a system proportional
to the device’s risk class, integrated into their QMS. This system actively collects, records
and analyzes relevant data on device quality, performance and safety throughout its
lifecycle. The data collected is used for various purposes, including updating benefit–risk
assessments, improving risk management and identifying preventive or corrective actions
when necessary. Manufacturers must inform relevant authorities when corrective actions
are needed [43,52].
Article 85 of Regulation (EU) 2017/745 mandates that manufacturers of Class I devices
produce a post-market surveillance report summarizing results and conclusions, including
details of any preventive or corrective actions taken [11]. Manufacturers of Class IIa, IIb
and III devices must also produce periodic safety reports, updating them annually for
Class IIb and III devices and as needed for Class IIa devices. For Class III and implantable
devices, manufacturers must submit safety reports to the NBs participating in the conformity assessments, while for other devices, reports are provided to the relevant NBs and
competent authorities upon request [43,52].
This comprehensive framework ensures the ongoing monitoring of medical devices’
safety and performance post-commercialization, facilitating the timely identification and
management of any issues that may arise [11]. Table 1 provides an overview of the
classification and regulatory requirements pre- and post-market for medical devices in
the EU.
Appl. Sci. 2024, 14, 9304
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Table 1. Medical devices’ classification and regulatory requirements in EU.
Class
I
Sub-Class
Definition
Pre-Market
I
Low risk
Technical documentation
Isp
Sterile device
Imf
Measuring device
Irs
Reusable surgical
instruments
Technical documentation with
Product quality assurance
OR
Technical documentation with
limited QMS
IIa
Low–medium risk
Devices installed within the
body in the short term
Technical documentation with full QMS
OR
Technical documentation with
Product quality assurance
OR
Technical documentation with product
verification
Medium–high risk
Devices installed within the
body for longer periods
Technical documentation with full QMS
OR
EC-type examination with
Product quality assurance
OR
EC-type examination with
Product verification
High risk
Technical documentation with full QMS
OR
EC-type examination with
Product quality assurance
OR
EC-type examination with
Product verification
II
IIb
III
-
Post-Market
Post-market
surveillance report
Periodic safety reports
(as needed)
Periodic safety reports
(annually)
Periodic safety reports
(annually)
AND
Safety reports
submission to NB
4.2. United States of America
In the USA, the regulation of medical devices falls under the jurisdiction of the Food
and Drug Administration (FDA) [12]. The approval and oversight process for these products is governed by the Federal Food, Drug and Cosmetic Act (FFDCA) [53].
4.2.1. Definition and Classification
A medical device is defined by the FDA as “an instrument, apparatus, implement,
machine, contrivance, implant, in vitro reagent, or other similar or related article, including
a component part or accessory which is recognized in the official National Formulary, or
the USA Pharmacopoeia, or any supplement to them, intended for use in the diagnosis of
disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease,
in man or other animals, or intended to affect the structure or any function of the body of
man or other animals and which does not achieve its primary intended purposes through
chemical action within or on the body of man or other animals and which is not dependent
upon being metabolized for the achievement of any of its primary intended purposes” [12].
The FDA classifies medical devices into three classes based on the level of risk they
pose to patients and the necessity of regulatory controls to ensure their safety and effectiveness [54]. Class I devices are those that do not support or sustain life and do not present
a potential unreasonable risk of illness or injury. These devices are considered to be of
low risk. They are subject to the least regulatory control and must comply with general
controls, which include provisions such as proper branding, labelling and adherence to
Good Manufacturing Practices (GMP) [54,55]. Class II devices are considered to be of
Appl. Sci. 2024, 14, 9304
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moderate risk. General controls alone are insufficient in assuring safety and effectiveness,
so they need to be subject to additional regulatory controls called special controls. These
controls may include performance standards, post-market surveillance, patient registries
and guidance documents. Lastly, Class III devices are those that support or sustain human
life, are of substantial importance in preventing the impairment of human health or which
present a potential unreasonable risk of illness or injury. These devices are subject to the
highest level of regulatory control, including pre-market approval (PMA), which requires
evidence providing a reasonable assurance of the device’s safety and effectiveness [54,55].
4.2.2. Market Authorization
All medical devices are subject to basic regulatory requirements known as general
controls, which provide a reasonable assurance of a device’s safety and effectiveness. As
the risk associated with a device increases, additional regulatory requirements, such as
special controls and premarket approval, are implemented [55,56].
Section 510(k) of the FFDCA is a regulatory pathway used by the FDA to clear medical
devices for market entry by demonstrating substantial equivalence to a legally marketed
predicate device. This process requires manufacturers to show that their new device has
the same intended use and technological characteristics as a predicate device, or that any
differences do not raise new questions of safety and effectiveness. The 510(k) process
begins with the submission of a detailed application to the FDA. This application includes
a description of the device, identification of the predicate device, an explanation of the
intended use and a comparative analysis of the technological characteristics of the predicate
device [56,57].
To expedite reviews for certain modifications, the FDA offers two alternatives to tradiAppl. Sci. 2024, 14, x FOR PEER REVIEW
13 of 25
tional submission 510(k): special 510(k) and abbreviated 510(k) pathways. These two forms
were introduced to simplify and speed up the approval process for medical devices. Special
510(k) applies to modifications of a manufacturer’s own legally marketed device, allowing
allowing
a morereview
efficient
review
changes
that do
affect intended
the device’s
for a morefor
efficient
process
forprocess
changesfor
that
do not affect
thenot
device’s
use
or fundamental
technology. Abbreviated
utilizes510(k)
FDA guidance
documents,
special
intended
use or fundamental
technology.510(k)
Abbreviated
utilizes FDA
guidance
doccontrols,special
or consensus
standards
to demonstrate
equivalence,
thereby
streamuments,
controls,
or consensus
standards substantial
to demonstrate
substantial
equivalence,
lining the
review process
[57]. Figure
7 compiles
the three
types of
as
thereby
streamlining
the review
process
[57]. Figure
7 compiles
the510(k)
three submissions,
types of 510(k)
well as when as
each
pathway
be used. should be used.
submissions,
well
as whenshould
each pathway
Figure
Figure 7.
7. 510(k)
510(k) submission
submission pathways:
pathways: traditional,
traditional,special
special and
and abbreviated
abbreviated [39].
[39].
For devices
devicesthat
thatdo
donot
nothave
have
a substantially
equivalent
predicate
device,
manufacFor
a substantially
equivalent
predicate
device,
manufacturturers
pursue
novo
classification
pathway,where
wherethe
theFDA
FDAconducts
conductsaa thorough
thorough
ers
cancan
pursue
thethe
de de
novo
classification
pathway,
review to
to evaluate
evaluate the
the device’s
device’s risks
risks and
and benefits.
benefits. This
This process
process is
is crucial
crucial for
for introducing
introducing
review
innovative
technologies
or
devices
into
the
market
that
do
not
fit
existing
classifications
[58].
innovative technologies or devices into the market that do not fit existing classifications
The
outcome
of
this
review
determines
the
device’s
risk
classification
(Class
I,
II
or
III).
If
[58]. The outcome of this review determines the device’s risk classification (Class I, II or
III). If classified as Class I or II, the device can be marketed immediately and may serve as
a predicate device for future 510(k) submissions, enabling similar devices to follow a
streamlined approval process. As mentioned, special controls are additional regulatory
requirements imposed on Class II devices to enhance their safety and effectiveness. These
controls can include performance standards, post-market surveillance, patient registries,
Appl. Sci. 2024, 14, 9304
13 of 24
classified as Class I or II, the device can be marketed immediately and may serve as a predicate device for future 510(k) submissions, enabling similar devices to follow a streamlined
approval process. As mentioned, special controls are additional regulatory requirements
imposed on Class II devices to enhance their safety and effectiveness. These controls
can include performance standards, post-market surveillance, patient registries, special
labelling requirements, pre-market data requirements and specific guidelines tailored to
the device type [55,59].
The PMA is the most rigorous pathway for FDA approval, focusing extensively on
demonstrating the safety and effectiveness of the device through comprehensive scientific
evidence. This includes detailed documentation of both administrative aspects and scientific research. The submission must adhere to strict regulations outlined in the FDA’s
framework, covering non-clinical research such as microbiology, toxicology and biocompatibility, as well as clinical research encompassing study protocols, safety data and patient
outcomes. Consequently, manufacturers must meticulously prepare their PMA applications
to address all regulatory requirements and scientific criteria. The failure to meet these
standards can result in the denial of the PMA, effectively inhibiting the device from being
marketed in the USA [55,60].
Class I devices are subject to the least stringent requirements due to their perceived
low risk [22]. These devices are not subjected to special controls and have no specific
requirements. They are exempt from Pre-Market Notification (510(k) submission) and only
need to comply with basic regulatory requirements, known as general controls [55,56].
Class II devices require more than general controls to ensure safety and effectiveness. To
enter the market, these devices typically go through the 510(k) process, demonstrating
substantial equivalence to a legally marketed predicate device. This involves submitting
Appl. Sci. 2024, 14, x FOR PEER REVIEW
14 of 25
detailed information to the FDA [59]. If no predicate exists, the de novo classification
pathway allows for a thorough FDA review to determine the device’s classification [58].
Special controls and the 510(k) process together ensure that Class II devices meet all the
necessary
necessarystandards
standardsbefore
beforebeing
beingmarketed
marketed[55,59].
[55,59].Introducing
IntroducingClass
ClassIII
IIImedical
medicaldevices
devices
into
intothe
theUSA
USAmarket
marketinvolves
involvesstringent
stringentregulatory
regulatoryprocesses
processesoverseen
overseenby
bythe
theFDA.
FDA.Unlike
Unlike
Class
ClassIIand
andClass
ClassIIIIdevices,
devices,which
whichmay
maybe
becleared
clearedthrough
throughthe
the510(k)-pathway
510(k)-pathwaybased
basedon
on
substantial
substantialequivalence
equivalencetotopredicate
predicatedevices,
devices,Class
ClassIII
IIIdevices
devicesrequire
requirePMA
PMA[56,57,60].
[56,57,60].
Unique
UniqueDevice
DeviceIdentification
Identification
TheUnique
UniqueDevice
Device
Identification
(UDI)
system,
established
byFDA
the Amendments
FDA AmendThe
Identification
(UDI)
system,
established
by the
ments
Actand
of 2007
anddefined
furtherby
defined
byand
the Drug
FoodAdministration
and Drug Administration
Safety and
Act
of 2007
further
the Food
Safety and Innovation
Act
of 2012, plays
a crucial
role ina identifying
tracking medical
devices throughout
their
Innovation
Act of
2012, plays
crucial roleand
in identifying
and tracking
medical devices
lifecycle
[61].their
Eachlifecycle
device has
distinct
UDIhas
alphanumeric
code
containing standardized
throughout
[61].a Each
device
a distinct UDI
alphanumeric
code containinformation,
allowing
the formalallowing
identification
of each
device and of
giving
detailed
ing standardized
information,
the formal
identification
each access
deviceto
and
giving
data
in the
Global Unique
Identification
(GUDID) [34,44,61,62].
Figure 8
access
to detailed
data inDevice
the Global
Unique Database
Device Identification
Database (GUDID)
provides
an example
an UDI in
USA. of an UDI in the USA.
[34,44,61,62].
Figure 8ofprovides
anthe
example
Figure8.8.USA
USAUDI
UDIexample
example[61].
[61].
Figure
The
TheUDI
UDIRule,
Rule,finalized
finalizedin
inSeptember
September2013,
2013,mandates
mandatesthat
thatmanufacturers
manufacturersinclude
includethe
the
UDI
UDIon
ondevice
devicelabels
labelsand
andpackages.
packages.For
Fordevices
devices requiring
requiringmultiple
multipleuses
uses and
and reprocessing,
reprocessing,
the
also
be be
marked
directly
on the
The information
associated
with UDIs,
theUDI
UDImust
must
also
marked
directly
on device.
the device.
The information
associated
with
UDIs, such as device attributes, production identifiers and Global Medical Device Nomenclature (GMDN) codes, is submitted to the FDA and enters the GUDID. This database
serves as a comprehensive reference system that is accessible to the public, enhancing
transparency and facilitating the better integration of device information into healthcare
data systems [55,63].
Appl. Sci. 2024, 14, 9304
14 of 24
such as device attributes, production identifiers and Global Medical Device Nomenclature
(GMDN) codes, is submitted to the FDA and enters the GUDID. This database serves as a
comprehensive reference system that is accessible to the public, enhancing transparency and
facilitating the better integration of device information into healthcare data systems [55,63].
This UDI system aims to enhance transparency and facilitate better integration into
healthcare data systems, with its objectives including reducing medical errors, improving
traceability and enabling effective post-market surveillance. By standardizing device
identification and providing comprehensive information through the GUDID, the FDA
supports patient safety and regulatory oversight [64].
4.2.3. Post-Market Surveillance
The FDA’s pre-market review process serves as an essential step in ensuring the
safety of medical devices before they reach the market [65]. However, a robust postmarket surveillance system is also essential to monitor device safety during clinical use and
facilitate corrective actions like updating labelling, enhancing user training or removing
devices from the market when issues arise [66]. The FDA’s post-market surveillance
includes mandated studies, adverse event reporting (or passive surveillance) that relies
on unsolicited reports of adverse events from manufacturers, users, importers and active
surveillance in real-world settings, which involves proactively collecting and analyzing
data from large healthcare systems to verify or detect safety signals [55,67].
Passive surveillance mechanisms like the Medical Device Reporting (MDR) system
identify significant adverse events and involves distinct reporting requirements for manufacturers, user facilities and importers. In 2014, the FDA mandated electronic Medical
Device Reporting (eMDR) to expedite access to adverse event information, although user
facilities may still submit paper MDR reports [68,69].
Active surveillance studies, such as post-market studies, such as “522 studies” and
Post-Approval Studies (PAS), address gaps in pre-market data and respond to safety
concerns. The FDA’s 522 Post-Market Surveillance Studies program encompasses responsibilities for designing, tracking, overseeing and reviewing studies mandated under section
522 of the FFDCA to ensure they are conducted effectively, efficiently and with a simple
approach [70]. The goal is to collect data that can uncover unforeseen adverse events
or other critical information necessary to protect public health and answer surveillance
questions. The PAS are mandatory for device approval and sponsors must employ valid
scientific methodologies in study design and conduct these studies effectively, efficiently
and with minimal burden. Failure to comply with any post-approval requirements may
lead to the FDA’s withdrawal of approval [67,70]. Table 2 presents a compilation of the
classification and regulatory requirements pre- and post-market for medical devices in
the USA.
Table 2. Medical devices’ classification and regulatory requirements in USA [54].
Class
Definition
Pre-Market
Post-Market
Medical Device Reporting
(Applicable to All Classes)
I
Low Risk
General Controls
II
Moderate
Risk
510(k) Submission
Special Controls
III
High Risk
Pre-Market Approval
(FDA Approval)
522 studies
(Applicable mainly to Class II and III)
Post-Approval Studies
(Applicable to All Classes)
4.3. Japan
Medical devices in Japan are regulated under the Act on Securing Quality, Efficacy and
Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products,
Appl. Sci. 2024, 14, 9304
15 of 24
Gene Therapy Products, and Cosmetics (PMD Act) by the Ministry of Health, Labour and
Welfare (MHLW) and the Pharmaceuticals and Medical Device Agency (PMDA). This act,
oversees the quality, efficacy and safety of medical devices by classifying them based on
the level of risk they pose to users [13,71].
4.3.1. Definition and Classification
According to the PMD Act, medical devices are “appliances or instruments”, etc.
which are intended for use in the diagnosis, treatment or prevention of disease in humans
or animals, or intended to affect the structure or functioning of the bodies of humans or
animals (excluding regenerative medicine products) and which are specified by Cabinet
Order” [13].
The classification of medical devices is essential in determining the level of regulatory
control required [72]. General Medical Devices, classified as Class I, require self-declaration
by the manufacturer. In these devices, an approval of the product is not necessary, but
a marketing notification is required [72]. Controlled Medical Devices, classified as Class
II, require certification by a registered certification body. The certification criteria are
reviewed and approved by the MHLW, with guidance provided in review guidelines [72].
Higher-Risk Medical Devices, classified as Class III and Class IV, require approval by the
MHLW following a review by the PMDA. The approval criteria and review guidelines are
established to ensure the safety and efficacy of these devices [72].
4.3.2. Market Authorization
In Japan, the regulatory process for medical devices varies depending on their classification and associated risks [73]. To facilitate the regulatory review process, the MHLW
issues comprehensive review guidelines that provide manufacturers with detailed insights
into the major technical requirements, acceptance criteria and evaluation criteria employed
by regulatory authorities. While these guidelines do not give specific performance limits,
they play a crucial role in promoting a more efficient and transparent review process. By
adhering to these guidelines, manufacturers can simplify the regulatory approval process
and expedite the entry of their medical devices into the Japanese market [74,75].
The Self-Declaration Process applies to the lowest risk devices. In this process, the
manufacturers must submit a DoC to the PMDA. This declaration asserts that the device
complies with relevant regulatory standards. While there is no formal review by regulatory
authorities, adherence to these standards is mandatory to ensure the safety and efficacy [73].
Third-Party Certification, which is required for controlled risk devices, involves certification by independent organizations registered by the MHLW. These certification bodies
evaluate the device’s design, manufacturing processes and quality control measures to
ensure compliance with established standards for quality, efficacy and safety [72]. They
also notify the MHLW of certification decisions, ensuring transparency and accountability
in the certification process. The process where there is an MHLW’s Approval and it is
reviewed by the PMDA is mandatory for higher-risk devices. The PMDA oversees this
process, evaluating devices against specific approval criteria. These criteria are often based
on international standards such as ISO or IEC, ensuring a thorough assessment of device
safety, efficacy and quality. The PMDA’s rigorous evaluation aims to protect public health
by ensuring that medical devices meet stringent regulatory requirements before entering
the market [72].
Class I device’s manufacturers undergo the self-declaration process, submitting a DoC
to the PMDA to assert compliance with regulatory standards. This process emphasizes
self-certification with mandatory adherence to ensure device safety and efficacy [72]. For
class II devices, a third-party certification is required. Certification bodies evaluate the
device’s design, manufacturing practices and quality controls to certify compliance with
standards for quality, efficacy and safety. Transparency is ensured through reporting to
the MHLW [72]. Class III and IV devices need approval from the MHLW, reviewed by the
PMDA. The PMDA evaluates these devices against specific approval criteria, often aligning
Appl. Sci. 2024, 14, 9304
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with international standards. This stringent evaluation ensures devices meet rigorous
safety, efficacy and quality standards before market entry [72].
Japanese Medical Device Nomenclature
The Japanese Medical Device Nomenclature (JMDN) is a standardized system used to
identify medical devices in Japan. It was created based on the 2003 version of the GMDN
and was implemented in 2005 [14,72].
Each medical device is uniquely identified by an eight-digit JMDN code. Codes
starting with 1, 3, or 4 are based on GMDN, while those starting with 7 are unique to
JMDN. The first five digits are derived from the GMDN code, with an additional three
digits appended to form the JMDN code. If the last three digits are 000, it means the GMDN
is not subdivided. The first of the three added digits indicate the presence of biological
materials or drug substances. The second digit reflects no differences in risk classification,
but there may be minor differences in the device. The third digit indicates the differences
Appl. Sci. 2024, 14, x FOR PEER REVIEW
of 25
in risk classification [72]. Figure 9 provides a comprehensive outline of the JMDN17code,
along with some examples.
Figure9.9.Outline
Outlineof
ofthe
theJMDN
JMDNcode
code[72].
[72].
Figure
The
simultaneously
with
thethe
current
GMDN.
TheThe
MHLW
creates
TheJMDN
JMDNisisnot
notupdated
updated
simultaneously
with
current
GMDN.
MHLW
crenew
codescodes
by referring
to the
GMDN
when
a medical
device
doesdoes
not not
fit
ates JMDN
new JMDN
by referring
tocurrent
the current
GMDN
when
a medical
device
any
existing
JMDN.
This
system
ensures
that
medical
devices
in
Japan
are
categorized
fit any existing JMDN. This system ensures that medical devices in Japan are categorized
and
andidentified
identifiedin
inaastandardized
standardizedmanner,
manner,facilitating
facilitatingregulatory
regulatoryprocesses
processesand
andensuring
ensuring
consistency
consistencywith
withinternational
internationalstandards
standardswhere
whereapplicable
applicable[72].
[72].
4.3.3.
4.3.3.Post-Market
Post-MarketSurveillance
Surveillance
The
post-market
The post-marketsurveillance
surveillanceof
ofmedical
medicaldevices
devicesin
inJapan
Japanisisaacomprehensive
comprehensivesystem
system
designed
to
ensure
the
ongoing
safety
and
effectiveness
of
these
products
designed to ensure the ongoing safety and effectiveness of these productsafter
afterthey
theyhave
have
been approved for use [76]. Initially, manufacturers must monitor and report any adbeen approved for use [76]. Initially, manufacturers must monitor and report any adverse
verse occurrences linked to their medical devices to regulatory bodies, like MWLH. These
occurrences linked to their medical devices to regulatory bodies, like MWLH. These inciincidents encompass device malfunctions and adverse reactions arising during device utidents encompass device malfunctions and adverse reactions arising during device utililization. Moreover, regulatory bodies regularly revise regulations and guidelines pertaining
zation. Moreover, regulatory bodies regularly revise regulations and guidelines pertainto medical devices to address emerging safety concerns and technological advancements.
ing to medical devices to address emerging safety concerns and technological advanceThis ensures manufacturers’ compliance with prevailing regulatory standards [76].
ments. This ensures manufacturers’ compliance with prevailing regulatory standards [76].
Manufacturers are further obliged to establish and execute risk management systems
Manufacturers are further obliged to establish and execute risk management systems
to detect, evaluate and mitigate potential risks associated with their medical devices.
to detect, evaluate and mitigate potential risks associated with their medical devices. This
This entails conducting comprehensive risk assessments and implementing corrective
entails conducting comprehensive risk assessments and implementing corrective
measures as necessary to address any safety concerns. Periodic regulatory inspections
measures as necessary to address any safety concerns. Periodic regulatory inspections are
are undertaken to validate adherence to GMP standards and other regulatory mandates.
undertaken to validate adherence to GMP standards and other regulatory mandates.
These assessments serve to uphold the quality, safety and efficacy of medical devices manufactured in Japan [76].
Effective communication among manufacturers, regulatory authorities, healthcare
practitioners and patients is indispensable for sustaining post-market surveillance. This
Appl. Sci. 2024, 14, 9304
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These assessments serve to uphold the quality, safety and efficacy of medical devices
manufactured in Japan [76].
Effective communication among manufacturers, regulatory authorities, healthcare
practitioners and patients is indispensable for sustaining post-market surveillance. This
involves sharing information regarding safety updates, issuing recalls or corrective measures when needed and encouraging information exchange to facilitate informed decisionmaking. Table 3 provides an overview of the classification of medical devices and the
regulatory requirements pre- and post-market in Japan.
Table 3. Medical devices’ classification and regulatory requirements in Japan.
Class
Definition
Pre-Market
Post-Market
I
General medical
devices
Self-declaration process
Regulatory oversight
revision
II
Controlled
medical devices
Third party certification OR
Minister’s approval (review by
PMDA)
Risk management system
III/IV
High-risk medical
devices
Minister’s approval (review
by PMDA)
Periodic regulatory
inspection
5. Comparison and Global Challenges of Medical Device Regulations
The regulatory framework in the medical device’s major markets (i.e., Europe, USA
and Japan) differ significantly. However, each one is tailored with the main objective of
guaranteeing the safety, effectiveness and innovation of medical devices. Recognizing the
regulatory differences between these markets is essential to ensure compliance with local
requirements, since each region has specific rules governing product approval, safety and
quality. In this way, companies launch their medical devices efficiently and safely, meeting
the needs of each market. Legal problems and launch delays are also avoided.
5.1. Comparative Analysis of Medical Device Regulations across Major Markets
When comparing the regulatory frameworks for medical devices across the EU, USA
and Japan, several similarities and differences emerge. All three of these regions classify
medical devices based on risk, with varying classifications dictating the level of regulatory
scrutiny. Each region mandates compliance with specific regulatory controls: CE marking
and NB oversight in the EU, FDA clearance or approval in the USA and PMDA approval in
Japan. Post-market surveillance is a common requirement across all of these regions, focusing on monitoring device performance, safety reporting and regulatory updates [11–13].
However, notable differences exist. The EU’s regulatory framework emphasizes
decentralized procedures overseen by NBs and integration them through EUDAMED for
transparency and traceability [11,51]. Additionally, the fact that the EU is a union of several
countries introduces significant complexity into its regulatory system compared to the US
and Japan. Although all the EU countries operate under the same regulations, variations
can arise in their interpretation and application. The USA system, overseen by the FDA,
incorporates a structured classification into three risk-based classes with pathways like
510(k) and PMA, coupled with stringent adherence to the Current GMP for consistent
quality control [12,57,60]. In Japan, the system is characterized by rigorous evaluation
processes by the PMDA, alongside adherence to the JMDN for device classification [72].
There are deadlines set by the regulatory authorities for the review of medical devices,
which tend to extend with the complexity and risk level of the device. However, these deadlines are not strictly fixed and can vary due to various factors, such as delays resulting from
requests for additional information or the current workload of the regulatory authorities.
Overall, while each region prioritizes device safety and efficacy through distinct
regulatory approaches, they converge in their commitment to ensuring public health and
Appl. Sci. 2024, 14, 9304
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facilitating market access for medical innovations. Table 4 provides a comparison of medical
devices legislation across the major markets.
Table 4. Comparison of medical devices’ legislation between regions.
Region
Europe
USA
Japan
Authority
European Commission (Medical
Device Coordination Group)
Notified Bodies
National Authorities
European Medicines Agency
United States Food and Drug
Administration (Center for
Devices and
Radiological Health)
Ministry of Health, Labour
and Welfare
Pharmaceuticals and Medical
Devices Agency
Regulation
Regulation (EU) 2017/745
Federal Food, Drug and
Cosmetic Act de 1938 and
subsequent amendments
Pharmaceuticals and Medical
Devices Act
Classification
Class I, Isp, Imf, Irs, IIa, IIb and III
Based on Their Intended Purpose
and Intrinsic Risk
Class I, II and III
Based on the Level of Risk
They Pose to Consumers
Class I, II, III and IV
Based on the Level of Risk
Posed by the Device
Identification System
Unique Device Identification
Unique Device Identification
Japan Medical Device
Nomenclature
Pre-Market
Declaration of Conformity
Conformity Assessment
Conducted by a Notified Body
510(k)
Special Controls
Pre-Market Approval
Self-Declaration
Third Party Certification
Minister’s Approval
(Review by Pharmaceuticals
and Medical Devices Agency)
Post-Market Surveillance Report
Periodic Safety Reports
Medical Device Reporting
522 studies
Pos-Approval Studies
Regulatory Oversight
and Revision
Risk Management System
Periodic
Regulatory Inspections
Post-Market
5.2. Japan’s Medical Devices Lag: A Global Challenge in the Medical Devices’ Market
The medical device lag in Japan is a current global challenge. It refers to delays in
the approval and adoption of new medical devices, stemming from various regulatory
processes and other factors between Japan and the EU/USA [11]. Initially, this lag was
substantial, reaching nearly 3 years in the early 2000s [18]. However, efforts have been
undertaken to address this issue, resulting in gradual improvements over time. This
phenomenon can occur at multiple stages, including pre-market approval, post-market
surveillance or reimbursement processes [77].
Medical device lag stems from several key factors, including stringent regulatory
frameworks that vary between countries. While these standards are crucial for patient
safety, they can also lead to delays in approving new and innovative medical technologies [78]. Another significant contributor to medical device lag is the increasing complexity
of modern medical devices [19]. As technology advances, devices become more intricate,
incorporating sophisticated functionalities and materials. This complexity poses challenges
to existing regulatory systems, which must adapt and expand their evaluation processes
to adequately assess these advanced technologies. Consequently, the time required for
regulatory approval and market entry often extends due to the need for more thorough
evaluations and assessments [10,78].
Furthermore, global harmonization issues compound medical device lag. Variations
in regulatory requirements across different countries create barriers that hinder the simultaneous global introduction of new devices. Although there is an ongoing initiative that
aims to promote the convergence and alignment of regulatory practices, achieving full
harmonization remains an ongoing challenge [79].
The impact of medical device lag is multifaceted. Firstly, it limits patient access to
innovative and potentially life-saving medical technologies. Delays in the approval process
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mean that patients may have to wait longer for new treatments that could significantly
improve their health outcomes. Medical device lag also affects market competitiveness.
Manufacturers facing prolonged approval processes may find it challenging to compete
with the in regions with faster regulatory systems. This can hinder technological advancements in the healthcare industry and reduce the incentive for innovation [80].
To mitigate medical device lag, several strategies have been proposed and implemented. One of the key approaches is harmonization efforts. Collaborative initiatives strive
to harmonize global regulations and simplify approval processes, reducing the time it takes
for new devices to reach the market [77,78]. Regulatory reforms are also essential. Continuous updates and reforms to regulatory frameworks are necessary to adapt to the evolving
landscape of medical technology. These reforms can help reduce approval timelines and
improve the efficiency of the regulatory process [78].
6. Global Harmonization Initiatives for Medical Devices
Considering the differences in the regulatory framework for medical devices across
various markets and the medical device lag that results from these disparities, it is essential
to attempt to harmonize these procedures. Initiatives that aim for global regulatory harmonization are crucial, as they try to simplify international trade, reduce compliance costs
and accelerate the introduction of new innovative products on the market. Additionally, by
establishing common standards for safety and efficacy, these initiatives promote a more
efficient and predictable regulatory environment, ultimately benefiting manufacturers,
regulators and patients alike.
6.1. The Global Harmonization Task Force
The Global Harmonization Task Force (GHTF) was one of the first major global initiatives to promote the harmonization of medical device regulations. Originally formed by
representatives from five founding members from the EU, the USA, Canada and Japan, the
GHTF was an international working group with representatives from the regulated industry and from the medical device regulatory authorities [81,82]. Its goal was to standardize
regulatory approaches for ensuring the safety, efficacy and quality of medical devices,
through the development and distribution of unified guidance documents across different
regulatory frameworks [82]. This was achieved in September of 1992, when representatives
from Europe, Asia-Pacific and North America met in France to investigate the possibility
of forming a global consultative partnership. This gave rise to a working framework a
few months later and resulted in the organization’s inaugural meeting as the GHTF at
the beginning of 1993. The GHTF was discontinued in 2012. However, its guidelines and
principles continue to influence current regulations and have paved the way for subsequent
initiatives [81].
6.2. International Medical Device Regulators Forum
The International Medical Device Regulators Forum (IMDRF) was established in 2011
by its founding members, including regulatory authorities from Australia, Brazil, Canada,
China, the EU, Japan, the USA and the WHO [6]. Their objective was to further expedite
international harmonization and convergence in medical device regulations [81]. However,
it was not until February 2012 that the IMDRF was officially launched, marked by its
inaugural meeting in Singapore [81]. This event initiated the transition from the GHTF to
the IMDRF, continuing the mission to harmonize regulatory approaches and ensure the
safety, efficacy and quality of medical devices globally [6].
The IMDRF aims to promote the sharing of best practices, to support innovation and
to facilitate global trade of medical devices. They provide guidance for countries with
developing regulatory systems to gather insights from established frameworks, ultimately
contributing to the advancement of global health standards [6].
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7. Conclusions
Medical devices are essential equipment in the health sector. These are any devices
used to diagnose, treat, prevent or mitigate medical conditions. Their complexity can
vary based on their function and purpose, the technology involved, their interaction with
the human body and the associated risk. These products undergo a very demanding
development process to ensure the final device meets the desired standards for safety,
efficacy and quality.
Over the last few years, the medical devices market was characterized by intense
competition and a wide diversity of innovative products and has experienced significant
growth. Before being placed on the market, medical devices must be evaluated by the
competent regulatory authorities to guarantee that they meet legal requirements. These
evaluations are fundamental to ensuring that the devices are suitable for use on patients.
The regulatory framework for medical devices differs significantly across the major markets
(i.e., EU, USA and Japan). Each region has established robust regulatory systems tailored
to its unique healthcare landscape and regulatory philosophy. Despite their differences,
all three regions share a commitment to safeguarding public health through stringent
regulatory controls, which, while crucial for patient safety, also contribute to challenges
in the medical devices’ market. One of these challenges in the Japan’s medical devices
lag, which consists of delays in the approval and adoption of new medical technologies,
hindering patient access to innovative treatments and impacting market competitiveness.
Efforts to address medical device lag include global regulatory harmonization initiatives
that aim for streamline approval processes, reduce regulatory discrepancies and promote
faster global market access for innovative medical devices. The GHTF and the IMDRF are
two crucial organizations, among others, that contributed to this harmonization.
The future of medical devices is very promising. It is expected that, by integrating
fields of computer science, such as AI, machine learning and robotics, the accuracy of
diagnoses and treatments will be improved. Connected devices enable real-time remote
monitoring, allowing the tracking of patient conditions, and intervene more quickly. In
addition, it will become increasingly common for devices to be customized to suit the
individual needs of each patient, promoting precision medicine. Lastly, the economic
impact of these devices will also be significant, with the expectation of reduced costs and
greater accessibility. However, the need for the global harmonization of regulations will
continue to be a challenge.
Overall, this study aimed to elucidate the regulatory frameworks for medical devices
in the EU, the US and Japan. Despite their differences and challenges, these regions
share a common goal of protecting patients’ health through rigorous evaluation processes,
which serve as the foundation for ongoing improvements in medical device standards.
There is still much to be explored on this topic, as the future of medical devices looks
promising and predicts a significant impact on the health sector, both in terms of availability
and innovation.
Author Contributions: Conceptualization, M.P. and V.B.; investigation, M.P. and C.A.; writing—original
draft preparation, M.P., C.A. and V.B.; writing—review and editing, C.A., A.R.R. and V.B.; supervision,
F.V. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflicts of interest.
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