Fundamentals of Medical Device Regulation and In-Vitro Diagnostic Regulation

As of May 25th 2017, the Medical Device Regulation (MDR) and In-vitro Diagnostic Regulation (IVDR) entered into force. These regulations replace the EU directives (MDD, IVDD, and AIMD). On May 26th, 2020, the Regulation become mandate, on May 26th, 2022. 

The European Union Medical Device Regulation (MDR) and In Vitro Diagnostic Device Regulation (IVDR) mark a significant milestone in the landscape of healthcare regulations. Introduced to replace the previous Medical Device Directives, these stringent regulations have ushered in a new era of oversight and patient safety for medical devices and in vitro diagnostic products within the European Union. MDR and IVDR represent a comprehensive framework that aims to ensure the quality, safety, and performance of medical devices and diagnostic tools while strengthening transparency and traceability throughout the supply chain. The extensive requirements and conformity procedures outlined in these regulations have not only reshaped the medical device industry but also set a global benchmark for regulatory standards, fostering innovation, and bolstering patient confidence in the products they rely on for their well-being.

What is new? Under These regulation (MDR 2017/745 & IVDR 2017/746)

• Essential requirements: The essential requirements – now renamed as “General safety and performance requirements” – are much more specific. Consequently, the technical documentation is closer regulated.
• UDI & Labeling: Like the FDA, manufacturers now must assign a unique device identification (UDI). This UDI consists of a device identifier and a production identifier. The UDI is not the only change to the labeling requirements.
• New roles: Manufacturers must employ (exception for small companies) a “person responsible for regulatory compliance”. Other "economic operators" include roles such as the distributor, the EU representative and the importer.
• EUDAMED: Not only the UDI data must be submitted to the EU database (EUDAMED), but also (dependent on the class) post-market data (e.g. a “periodic safety update report”) .
• Clinical Evaluation and PMCF (post-market clinical follow-up): The MDD was addressing the clinical evaluation only on one page and the post-market clinical follow up (PMCF) not at all. The MDR exactly describes respective requirements in several articles and a comprehensive annex.
• Post-Market Surveillance: The post-market surveillance, that was barely addressed in MDR, now is regulated in detail.
• Placing on the market, conformity assessment procedures: The conformity assessment procedures were changed: There is no longer a procedure comparable to Annex VI of MDD. Additionally, for high risk products (some class IIa and most of class III products) additional procedures must be followed and the notified bodies must consult expert groups/panels (scrutiny).
• Classification: The classification rules now take active implantable devices, nano-materials, and substances introduced into the body into account. A new classification rule 11 specifically addresses software – major reclassifications are expected.
• Common specifications: The EU commission entitles itself to introduce “common specifications” (CS) if harmonized standards are lacking or insufficient. So far there is no standard harmonized nor any CS published.
• No regulatory authority/agency: There won’t be a European agency granting market access comparable to the European Medicine Agency EMA for drugs or the FDA for drugs, medical devices and more.
• Manufacturers still declare conformance (with the CE mark) after following a conformity assessment procedure. The conformity assessment procedures still depend on the class of the devices. With exception of class I devices, notified bodies still have to be involved.
• The classification essentially is unchanged. Exceptions are mentioned below.
• Harmonized standards remain a way of proofing compliance. However, the EU additionally introduces the concept of “common specification”.
• Non-EU-manufacturers can import medical devices. One of the prerequisites still is an EU representative.

The Medical Device Regulation (MDR) and In Vitro Diagnostic Device Regulation (IVDR) are comprehensive legislative frameworks comprising several key chapters, each addressing specific aspects of medical devices and in vitro diagnostics. These regulations cover essential elements such as product classification, clinical evaluation, post-market surveillance, and market surveillance. The chapters also delve into matters concerning conformity assessment procedures, including the role of notified bodies, and provide guidance on the documentation and technical requirements for manufacturers. Additionally, MDR and IVDR emphasize the importance of post-market activities, vigilance reporting, and market surveillance to ensure ongoing product safety and performance. Furthermore, they establish clear rules for clinical investigations, addressing the clinical evidence necessary to support product safety and efficacy. Overall, the chapters of MDR and IVDR work in unison to create a robust regulatory framework that prioritizes patient safety, product quality, and public health while stimulating innovation and technological advancements in the medical device and in vitro diagnostic sectors.

Contents of the MDR (2017/745) & IVDR (2017/746)
Chapter I	Introductory provisions
Chapter II	Making available on the market, and putting into service of devices, obligations of economic operators, CE Marking, free movement
Chapter III	Identification and traceability of devices, registration of devices and economic operators, summary of safety and clinical performance, European database on medical devices
Chapter IV	Notified bodies
Chapter V	Classification and conformity assessment
Chapter VI	Clinical evidence, performance evaluation and performance studies
Chapter VII	Post-market surveillance, vigilance and market surveillance
Chapter VIII	Cooperation between member states, medical device coordination group, EU reference laboratories and device registers
Chapter IX	Confidentiality, data protection, funding and penalties
Chapter X	Final provisions

The Annexes in the Medical Device Regulation (MDR) and In Vitro Diagnostic Device Regulation (IVDR) serve as critical components that provide detailed guidelines, specifications, and essential information for the implementation of these regulatory frameworks. These annexes cover a wide range of topics, including common technical specifications, clinical evaluation, classification criteria, and conformity assessment procedures. They offer manufacturers, notified bodies, and competent authorities specific insights into the standards, procedures, and requirements that apply to medical devices and in vitro diagnostic devices.

Annexes in the MDR and IVDR help ensure consistency and clarity in the application of the regulations, aiding manufacturers in understanding what is expected from them and how they should proceed with regulatory compliance. Furthermore, they play a crucial role in harmonizing the interpretation and enforcement of the regulations across the European Union, facilitating the free movement of safe and effective medical devices and in vitro diagnostic devices within the single market.

List of Annexures	MDR (2017/745)	IVDR (2017/746)
Annex I.	General safety and performance requirements
Annex II.	Technical documentation
Annex III.	Technical documentation on post-market surveillance
Annex IV.	EU Declaration of conformity
Annex V.	CE marking of conformity
Annex VI.	Information to be submitted upon the registration of devices and economic Operators in accordance with articles 29(4) and 31, core data elements to be provided To the UDI database together with the UDI-DI In accordance with articles 28 and 29, And the UDI system	Information to be submitted upon the registration of devices and economic operators in accordance with articles 26(3) and 28, core data elements to be included in the UDI database together with UDI-DI in accordance with Articles 25 and 26 of the UDI system
Annex VII.	Requirements to be met by notified bodies
Annex VIII.	Classification rules
Annex IX.	Conformity assessment based on a quality management system and assessment of the technical documentation
Annex X.	Conformity assessment based on type examination
Annex XI.	Conformity assessment based on product conformity verification	Conformity assessment based on production quality assurance
Annex XII.	Certificates issued by a notified body
Annex XIII.	Procedure for custom-made devices	Performance evaluation, performance studies and post-market performance follow-up
Annex XIV.	Clinical evaluation and post-market clinical follow-up	Interventional clinical studies and certain other performance studies
Annex XV.	Clinical investigations	Correlation table (with the IVDD)
Annex XVI.	List of groups of products without an intended medical purpose referred to in Article 1(2)	--
Annex XVII.	Correlation table (with MDD & AIMD)	--

What MDR & IVDR Says About QMS

The Medical Device Regulation (MDR) and In Vitro Diagnostic Device Regulation (IVDR) include several provisions and requirements related to the establishment and maintenance of a Quality Management System (QMS) by manufacturers. The QMS is a fundamental aspect of ensuring the safety and performance of medical devices and in vitro diagnostic devices in the European market. Here are some key aspects of what MDR and IVDR say about QMS:

S. No.	MDR	IVDR
1	A strategy for regulatory compliance, including compliance with conformity assessment procedures and procedures for the management of modifications to the devices covered by the system;
2	Identification of applicable general safety and performance requirements and exploration of options to address those requirements;
3	Responsibility of the management;
4	Resource management, including selection and control of suppliers and subcontractors;
5	Risk management as set out in Section 3 of Annex I;
6	Clinical evaluation in accordance with Article 61 and Annex XIV, including post-market surveillance follow-up (PMS).		Performance evaluation, in accordance with Article 56 and Annex XIII, including PMPF.
7	Product realization, including planning, design, development, production and service provision;
8	Verification of the UDI assignments made in accordance with Article 27(3) to all relevant devices and ensuring consistency and validity of the information provided in accordance with Article 29;		Verification of the UDI assignments made in accordance with Article 24(3) to all relevant devices and ensuring consistency and validity of information provided in accordance with Article 26.
9	Setting-up, implementation and maintenance of a post-market surveillance system, in accordance with Article 83;		Setting-up, implementation and maintenance of a post-market surveillance system, in accordance with Article 78.
10	Handling communication with competent authorities, notified bodies, other economic operators, customers and/or other stakeholders;
11	Processes for reporting of serious incidents and field safety corrective actions in the context of vigilance;
12	Management of corrective and preventive actions and verification of their effectiveness;
13	Processes for monitoring and measurement of output, data analysis and product improvement.

Requirements for Different Sectors

• European Medical Device Regulation (EU MDR) and the European In Vitro Diagnostic Regulation (EU IVDR), both regulations use the term “economic operator”.

That’s because economic operators are the entities that make up the medical device supply chain. Manufacturers, authorized representatives, importers, and distributors all play a role in ensuring that safe, high-quality medical devices make it to their end users.

Manufacturers

Manufacturers are at the heart of the medical device supply chain. They are responsible for designing, developing, manufacturing, and labeling medical devices in compliance with the regulations. Their primary responsibilities include:

• Quality Management System (QMS): Manufacturers must establish and maintain a robust Quality Management System (QMS) that ensures the safety and performance of their devices. This system should cover design and manufacturing processes.
• Clinical Evidence: For some devices, clinical evidence is necessary to demonstrate their safety and performance. Manufacturers must collect and maintain clinical data throughout the product lifecycle.
• Risk Management: Identifying, assessing, and mitigating risks associated with their devices is a fundamental responsibility of manufacturers.
• Technical Documentation: Manufacturers are required to create and maintain comprehensive technical documentation, including information about device design, testing, and conformity with regulations.
• Post-Market Surveillance (PMS): Manufacturers must establish systems for continuous monitoring of their devices once they are in the market, reporting any issues or incidents.

EU Authorized Representative

The EU Authorized Representative acts as a liaison between non-European manufacturers and European regulatory authorities. Their responsibilities include:

• Regulatory Compliance: They ensure that the manufacturer's devices comply with EU MDR and IVDR requirements.
• Documentation Handling: Authorized representatives maintain the technical documentation and are responsible for making it available to competent authorities upon request.
• Incident Reporting: They assist manufacturers in reporting incidents and field safety corrective actions to the competent authorities.

Before Appointing the manufacturer consider the following

• The Authorized Representative has access to the full technical documentation, including information on the project,
• An Authorized Representative should be kept informed of any changes in legal regulations and should warn your company of the changes well in advance,
• The Authorized Representative should be able to represent the manufacturer adequately and answer all questions from the competent authorities concerning the manufacturer’s medical devices,
• The Authorized Representative is appointed in all information materials: labels, packaging, instructions for use.

Distributer/Importer/Service Partner

These entities ensure that the medical devices are effectively distributed and reach the end users in a safe and efficient manner. Their responsibilities include:

• Ensuring Traceability: They must establish and maintain systems to ensure the traceability of devices, making it possible to recall devices if necessary.
• Storage and Handling: Distributors and importers should store and handle devices in a way that preserves their integrity and safety.
• Servicing and Repackaging: Service partners may also be involved in the maintenance, servicing, and repackaging of devices, ensuring that they continue to meet regulatory requirements.
• Incident Reporting: Distributors and importers should report incidents or any concerns regarding device safety to the manufacturer and competent authorities.

Must Ensure

• The product has a CE marking.
• A declaration of conformity has been issued for the product.
• The device is accompanied with all of the information to be supplied by the manufacturer.
• The name and address of the importer is on the product, packaging, or accompanying information.
• The manufacturer has issued a unique device identifier (UDI).
• The product appears to conform to all requirements of the Regulation.

RESPONSIBILITIES

• Keeping a record of complaints. Not only do distributors have to keep a record of complaints from healthcare professionals and patients, they must also immediately forward that information to the manufacturer and, in some cases, the authorized representative and importer.
• Informing the manufacturer of any non-conformances. Again, the regulations state that when distributors believe a device is not in conformance with regulations, they “shall inform the manufacturer and, where applicable, the manufacturer’s authorized representative, and the importer.”
• Reporting serious incidents or serious risks to competent authorities. In the case of serious risk or incidents, the distributor must also inform the competent authority of their respective member state. Additionally, distributors must be ready to provide all of their documentation demonstrating the conformity of a device to the competent authority upon request.
• Achieving a high level of traceability of devices. The regulations also state that distributors must be able to identify for competent authorities:
• Every economic operator they supplied a device to
• Every economic operator that supplied them a device
• Every healthcare professional or institution they have directly supplied a device

Non-Medical Products within scope of MDR

According to Article 1(2), the new Regulation 2017/745 shall apply to certain non-medical devices, as listed in MDR Annex XVI, which present the same characteristics and risk profile as analogous medical devices under the scope of the Regulation. Like

• Contact lenses
• Products intended to be introduced into the human body through surgically invasive means
• Facial dermal fillers
• Equipment for liposuction
• Lasers for skin resurfacing, tattoo or hair removal
• Equipment for electromagnetic brain stimulation
• Emitting equipment intended for use on the human body
• Devices for the control or support of conception, regardless of whether intended to be used for a medical purpose

Conformity Assesment Under MDR & IVDR

Conformity assessment is a critical process within the European Medical Device Regulation (EU MDR) and the European In Vitro Diagnostic Regulation (EU IVDR). It ensures that medical devices and in vitro diagnostic devices placed on the European market meet the regulatory requirements and adhere to the highest standards of safety and performance. Here's an overview of conformity assessment in the context of these regulations:

According to the MDR, conformity assessment is a procedure that determines whether the requirements of the MDR for the medical device have been met. Before manufacturers place a medical device on the market, this conformity assessment must be performed with a positive result. The MDR specifies the applicable conformity assessment procedures for this in Annex IX to XI. A conformity assessment must also be carried out when a manufacturer puts a product into service that has not yet been placed on the market. Only after successful conformity assessment, a manufacturer may affix the CE marking on his medical devices.

Conformity Assessment Procedures: 

EU MDR and IVDR define different conformity assessment procedures based on the class and risk of the device,There are different types of conformity assessment procedures:

• Conformity assessment based on a quality management system and technical documentation assessment (Annex IX)
• Conformity assessment based on type examination (Annex X)
• Conformity assessment based on product conformity testing (Annex XI)
• Self-Certification (Class I Devices): Manufacturers of low-risk devices can self-certify compliance with the regulations and affix the CE mark.
• Involvement of a Notified Body (Class IIa, IIb, III, and IV Devices): Higher-risk devices require the intervention of a Notified Body. The Notified Body reviews technical documentation, conducts audits, and issues the CE certificate if all requirements are met.
• Performance Studies and Clinical Evidence: For certain high-risk devices, clinical evidence and performance studies may be required to demonstrate safety and efficacy.

The primary goal of conformity assessment is to confirm that a medical device or in vitro diagnostic device complies with the essential requirements and specifications outlined in the regulations. It is a thorough evaluation process that includes technical documentation review, quality management system assessment, and, in some cases, involvement of Notified Bodies.

Role of Notified Bodies: Notified Bodies are independent organizations designated by EU member states to assess and certify the conformity of medical devices and in vitro diagnostic devices. They play a crucial role in the conformity assessment process. Notified Bodies assess high-risk devices, including class III and implantable devices. Their responsibilities include:Reviewing technical documentation and quality management systems.

• Conducting audits of manufacturers to ensure compliance.
• Assessing clinical data and performance evaluations.
• Granting or withdrawing the necessary certificates.

Once a medical device or in vitro diagnostic device successfully completes the conformity assessment process, it receives the CE mark. The CE mark indicates that the device complies with EU MDR and IVDR and can be legally marketed within the European Union.

Under MDR & IVDR, It is verified that whether the device meets all of the regulatory requirements for European Union medical devices; the certification is indicated by a CE Mark. In order for medical devices to be certified, company must implement a Quality Management System (QMS).