In Vitro Diagnostic Device Regulation in Europe: Update on Revisions

The transition from complying with the EU IVDD 98/79/EC to meeting the requirements of the new EU IVDR 2017/746 involves a substantial regulatory framework for in vitro diagnostic (IVD) medical devices to ensure their safety and quality. The enhanced regulatory framework to speed up the market release includes, but is not limited to, additional scrutiny by a notified body, risk classification and conformity assessment, vigilance and market surveillance, and performance evaluation and performance studies.

Introduction

The EU In Vitro Diagnostic Medical Device Regulation (EU IVDR 2017/746)¹ repealed the EU In Vitro Diagnostic Medical Device Directive (EU IVDD 98/79/EC) and came into effect on 26 May 2017, with 26 May 2022 as the date of application (DoA). The regulation will be effective in the 27 EU member states and three countries of the European Free Trade Association – Norway, Iceland, and Liechtenstein. In addition, Switzerland intends to implement a mutual recognition agreement with the EU, which will allow products that are compliant with the EU IVDR to be placed on the Swiss market.

The EU IVDR 2017/746¹ repealed the EU IVDD 98/79/EC and Commission Decision 2010/227/EU. The focus of the new and revised regulation includes:

• A rule-based classification system,
• Stringent requirements for clinical evidence and postmarket performance follow-up, and
• The implementation of a unique device identifier (UDI) to ensure traceability of devices.
   

Transition provisions in the EU 2023/607 regulation²

The EU IVDR transitional provisions help manufacturers comply with the requirements of the new regulation. In March 2023, the EU 2023/607 regulation was amended with a revised timeline for the complete transition from the EU IVDD to the EU IVDR. This new timeline allows increased flexibility for manufacturers and notified bodies to ensure patient safety. However, there was no change to the DoA, 26 May 2022, so the EU IVDR vigilance and postmarket surveillance (PMS) requirements have been applicable since that date.

Under Article 110(3), as amended by Regulation (EU) 2022/1121,³ in vitro diagnostic devices (IVDs) can be put into service after the 26 May 2022 DoA until the end of the revised transition periods (Table 1) under the following conditions:

• All IVDs must have Conformité Européenne (CE) marking as of 26 May 2022 and should be registered with the European Database on Medical Devices (EUDAMED) when operational;  
• There are no significant changes to the device design or their intended purpose after the EU IVDR’s DoA, and they should therefore remain in compliance with the EU IVDD requirements; and  
• The manufacturer must comply with the general obligations of the EU IVDR – that is, PMS and vigilance requirements – and the economic operators’ registration.

Furthermore, IVDs placed on the market before 26 May 2022 in compliance with the EU IVDD can remain on the market without a legal time restriction. Therefore, the transitional provision amended Article 110(4) of the EU IVDR and removes the sell-off period (26 May 2025 to 26 May 2028) requirement to prevent redundant disposal of in vitro devices that are still in the supply chain. Figure 1 shows the proposed new EU IVDR timeline under the EU 2023/607 regulation.

Figure 1. Proposed EU IVDR timeline under EU 2023/607²



EU IVDD, EU In Vitro Diagnostic Medical Device Directive; EU IVDR, EU In Vitro Diagnostic Medical Device Regulation.

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IVD classification

In accordance with Article 47 of the EU IVDR, IVDs are classified into Classes A, B, C, and D based on their intended use and inherent risks, which span both individual and public health risks. Class D devices are the highest risk, and Class A devices are the lowest risk. The Medical Device Coordination Group’s MDCG 2020-16⁴ guidance on classification rules for IVDs under the EU IVDR enforces the classification rules in Annex VIII based on the intended purpose of a device (Table 2).

Conformity assessment procedure¹

The conformity assessment procedure is an important step in launching an IVD in the market as per Article 48 of the EU IVDR. The conformity assessment procedure is provided in Annexes IX to XI depending on the risk class of the IVD, as outlined in Figure 2. The IVDs belonging to Class A (sterile), B, C, and D require a notified body’s involvement. The EU declaration of conformity is a formal document that officially confirms that the product fulfills all the necessary requirements of the CE marking.

Figure 2. Conformity assessment procedure^1a



DoC, declaration of conformity; IVD, in vitro diagnostic medical device; QMS, quality management system.

Note. Devices under Class A (nonsterile) do not need to meet the requirements listed in various annexes. They need only to have EU DoC (Article 17) plus technical documentation (Annexes II and III). Notified body intervention is not required for Class A (nonsterile) devices. Devices under Class A (sterile) must meet the requirements for Annex IX or Annex XI (sterile condition).

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Major changes regarding clinical evidence

Under Article 56, clinical evidence is required to support the intended purpose of the device and be based on a continuous process of performance evaluation, followed by a performance evaluation plan. The manufacturer is responsible for deciding how much clinical evidence is sufficient to affirm the safety of the device based on its intended purpose and class.

In accordance with Article 56 and with Annex XIII (Part A), a performance evaluation must be supported by data per the risk class of the device, any novel features, and availability of published literature to demonstrate the following listed clinical claims:

• Scientific validity
• Analytical performance
• Clinical performance

Therefore, clinical evidence is based on the data and conclusions drawn from the assessment of the aforementioned elements. Clinical evidence must be kept up to date to ensure the device remains state of the art.

Postmarket surveillance and vigilance

PMS is a key element of a manufacturer’s quality management system according to Article 10(8). A manufacturer is required to create, maintain, document, implement, and update a PMS in accordance with the risk class and appropriate for the type of IVD. EU IVDR PMS provisions may include:

• Documentation showing the data on the quality, performance, and safety of an IVD throughout its lifecycle.  
• Documentation drawing the required conclusions and determining, implementing, and monitoring any corrective and preventive actions.  
• Collection of data by the manufacturer’s PMS system to update the relevant characteristics of a device; for example, benefit-risk determination, labeling (labels and instructions for use), design and manufacturing information, and/or summary of safety and performance.  
• The requirement for a PMS plan is referred to in Article 79 of the EU IVDR 2017/746. The purpose of postmarket surveillance is to collect and use the information available for devices after receiving marketing approvals to identify any need for corrective or preventive actions on the device in the field.  
• Manufacturers of Class A and B devices are required to prepare and maintain a report summarizing results of the PMS data because of the PMS plan. The report should be made readily available to the notified bodies and competent authorities upon request (Article 80).  
• Manufacturers of Class C and D devices must establish and maintain a periodic safety update report (PSUR) as outlined in Article 86. PSURs for Class C and D devices must be updated at least annually.  
• PSURs for Class D devices must be submitted electronically to the notified body (Article 87).

Vigilance

Section 2 of Chapter VII of the EU IVDR lists the requirements for vigilance reporting. Some of the requirements stipulate:¹

• A manufacturer must report serious incidents (that are not related to patient death, unanticipated serious deterioration in the state of health, or serious public health threat) no later than 15 days after the manufacturer becomes aware of the event (Article 82 (3)).  
• The reports for the incidents related to serious public health threat must be reported immediately by the manufacturer, or no more than two days after the manufacturer becomes aware of the event (Article 82(4)).  
• Events related to a patient’s death or any unanticipated serious deterioration in a patient’s state of health must be reported immediately by the manufacturer, or no more than ten days after the manufacturer becomes aware of the event (Article 82(5)).  
• Trend reporting for nonserious incidents or those that are expected erroneous results must provide an explanatory statement (Article 83).  
• Procedures for evaluating IVDs that present an unacceptable risk to the health or safety of a patient and/or other noncompliance activities are provided in Articles 89 and 90.  
• A UDI database must be established to process and provide the UDI data so that it is accessible to the public.

Technical documentation¹

EU IVDR Annexes II and III list the requirements for technical documentation intended to be used for registration purposes for a device to be launched in the EU and outside the EU. Furthermore, technical documentation also covers the requirements for PMS as discussed in Annex III of the EU IVDR.

The requirements under the EU IVDR are more stringent and explicit than the requirements listed under the EU IVDD. Technical documentation is a living document that summarizes the design and manufacturing of a device in accordance with the general safety and performance requirements to ensure the benefits of a device outweigh the risks. The required content for the technical documentation for an IVD is provided in Figure 3.

Figure 3. Submission process and technical documentation under the EU IVDR¹

DI, device identifier; PMS, postmarket surveillance; PMSR, postmarket surveillance report; PSUR, periodic safety update report; UDI, unique device identifier.

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Conclusion

The new EU IVDR significantly changes the regulatory environment for the launch of a diagnostic device intended for human use in Europe. A greater understanding of the implications of the EU IVDR is required to help the manufacturer pursue EU certification. Some of the major effects of this transition are that:

• The conformity assessment procedure is based on quality or product-related aspects;
• Harmonized standards and common specifications must be used to define safety and performance requirements for an IVD;
• Manufacturers are obliged to comply with the PMS system requirements and vigilance reporting;
• It increases EUDAMED’s role in vigilance and surveillance activities and makes some of the information easily accessible to the public;
• More details are required for clinical evidence throughout the lifecycle of the device;
• Notified bodies are required for the review of all classes of IVDs. All classes of IVDs, except those in nonsterile Class A, require notified body approval; and
• New dates of application have been provided under Regulation EU 2023/607 based on the IVD class.

Abbreviations
CE, Conformité Européenne; DoA, date of application; EUDAMED, European Database on Medical Devices; EU IVDD, EU In Vitro Diagnostic Medical Device Directive; EU IVDR, EU In Vitro Diagnostic Medical Device Regulation; IVD, in vitro diagnostic device; MDCG, Medical Device Coordination Group; PMS, postmarket surveillance; PSUR, periodic safety update report; UDI, unique device identifier.

Source: RAPS