Major changes in In-vitro Device (IVD) regulation

1. Emergence of New Regulation, In Vitro Diagnostic Medical Devices Regulation 

In Vitro Diagnostic (IVD) companies that wish to enter European market is familiar with this term "Directive 98/79/EC" It was published in October 1998, and no matter what IVD companies are, they had to follow this directive to sell products in EU.

Yet, it has been adopted for more than 20 years and could not chase the speed of development of science technology. Also, there was a big scandal that evoked needs of the amendment. Therefore, the needs of tighten the regulation have been raised, and eventually the EU release new regulation named Regulation 2017/746.

What was "The scandal"

In 2012, there was an incident in which medical damage occurred due to a breast implant made of industrial silicone (As known as PIP scandal). Many of the patients developed cancer due to the accident, and as industrial silicon ruptured, it introduced into the body and caused complications, leading to life-threatening damage. The voice of the importance of securing the safety of medical devices has grown and in response to these concerns, the new legislation has been amended. This is the Regulation (EU) 2017/746, that we commonly know these days. The IVDR (In Vitro Diagnostic Medical Device Regulation) was revised to include stricter requirements than the IVDD (In Vitro Diagnostic Medical Device Directive). This new regulation, IVDR 2017/746, is effective from 26 May 2022.

Delay of adopting IVDR

The IVDR requirements do not change, and the DoA(Date of Application) remains May 26, 2022. Further, Class A non-sterile IVDs must still be IVDR compliant by the DoA (sell-off period until May 26, 2025). Nevertheless, Notified Body-issued IVDD CE Marking Certificates may remain valid until their expiration or May 27, 2025 at the latest (versus May 27, 2024), and transitional provisions for up-classified IVDs are extended based on risk classification in a progressive rollout.

The soft transitional provisions are as follows:

•          IVDD CE Marking Certificates (issued under the IVDD) may remain valid until their expiration or May 27, 2025 at the latest

•          IVDs that are self-certified under the IVDD but would require NB certification under the IVDR will have more time to obtain the required CE Marking Certificate (note they need to be placed on the market and have a DoC(Declaration of Conformity) signed to the IVDD before the IVDR DoA):

•          May 26, 2025 for Class D – sell-off period until May 26, 2026

•          May 26, 2026 for Class C – sell-off period until May 26, 2027

•          May 26, 2027 for Class B – sell-off period until May 26, 2028

•          May 26, 2027 for Class A sterile – sell-off period until May 26, 2028

The respective sell-off period is the time between the date when the devices must be placed on the EU market (in the hands of an EU distributor or there needs to be a sales agreement for the device with a customer) and the time when the device must be removed from the EU market if it is not with an EU customer.[1]

Why not right away?

1. Lack of Notified bodies

One of the main changes is participation of independent notified body. Currently, only a relatively small number of high-risk devices (approximately 8% of all in vitro diagnoses in the market) are subject to notified body management under Directive 98/79/EC.

According to regulations, approximately 80% of IVD medical devices will be under the control of notified bodies, and the majority will be under the control of notified bodies for the first time.

In other words, the manufacturer must complete the appropriate conformity assessment procedure before the device is released to the market before applying to the notified bodies and obtaining one or more certificates. According to a report, the conformity assessment process takes an average of one year, after which additional time (approximately six months) is required to produce devices and prepare them for market release.

2. Lack of preparation due to COVID-19

COVID-19 pandemic stroked the world. Data on market readiness collected by the European Commission during the first half of 2021 stated that Member States, health institutions, related organizations and economic operators will not be able to ensure the proper implementation and application of the Regulation from 26 May 2022.

Only 6 notified bodies have been designated so far under Regulation (EU) 2017/746. This is literally impossible for the manufacturer to perform the legally required conformity assessment procedures in a timely manner due to the lack of competence of the notified bodies.

Due to COVID-19 travel restrictions, it is difficult for notified bodies to conduct on-site audits at the manufacturer's premises to verify manufacturing and other relevant processes. Travel restrictions are still on going in many parts of the EU and still significantly hinder the proper performance of the notified body’s conformity assessment. Identifying these problems, the Competent authority (European Commission) delayed the timing of IVDR application.

2. Major revisions 

Due to the IVDD-IVDR transition, there are several revisions to the Regulation (EU) 2017/746. The major point is that IVDR is a law, not a directive. It means that it will be applied faster and will have more powerful sanctions on the healthcare industry. It can enact more detailed articles such as raising the notified bodies' cost or altering minor rules and the standard of risk class. There is a possibility that common specifications such as CS will be changed in the future.[1]

1) Scope of Classification of IVD

The definition of an IVDR device has been expanded too. In-direct medical purpose and the concept of life test including ‘predict were added to definition of IVD. Additionally, the classification based on the List (List A, B) has been changed and all IVDR devices are classified based on the risk-based classification system. Through the conformity assessment route, they will be granted the appropriate class, and most of the devices will get the evaluation by notified bodies as subject to permission. Because the concept of clinical performance investigation appeared in the IVDR regulatory system, the notified bodies will require more clinical evidence and the PMS system that manages the clinical evidence will be applied to medical device manufacturers. [1][2]

2) Person Responsible for Regulatory Compliance

Manufacturers must designate at least one staff member responsible for ensuring compliance to the IVDR as appropriate according to Article 15 of the Regulation. Exceptionally, Micro and small manufacturer shall not be required to have the person responsible for regulatory compliance within their organization but the person should be in proximity to the manufacturing site.

The person responsible for regulatory compliance (PRRC) shall have expertise in the field of in vitro diagnostic medical devices and professional experience. PRRC is responsible for ensuring that the devices are appropriately checked, in accordance with the quality management system before a device is released, the technical documentation and the EU declaration of conformity(DoC) are drawn up and kept up-to-date. In addition, The PRRC is required to report the obligations referred to in Articles 82 to 86. [1]

3) EUDAMED

EUDAMED means European Database on Medical Devices. Its role is to integrate different electronic systems to collate and process information regarding devices on the market, relevant economic operators, certain aspects of conformity assessment, notified bodies, certificates, performance studies, vigilance, and market surveillance. The objectives of EUDAMED are to enhance overall transparency, including through better access to information for the public and healthcare professionals, to avoid multiple reporting requirements, to enhance coordination between the Member States, and to streamline and facilitate the flow of information between economic operators, notified bodies or sponsors and the Member States [1]

4) UDI (Unique Device Identification) System

The unique device identification (UDI) system has been changed too. Not only the existing guidelines, GHTF N2R3 and EC guidelines is applied. UDI should be placed on the label of the device or its packaging. The form of UDI is a linear or 2D barcode that shall be recognizable to humans and the machine. This requirement is compatible with FDA registration. [1][2]

5. Notified Body

Lastly, notified bodies will be evaluated harder under IVDR. Due to the unfortunate incident as known as PIP scandal, demanding equity from these notified bodies is more robust than ever. All notified bodies shall strengthen their self-competence according to the required specification of the competency and the process. As a result, it is expected that a significant number of notified bodies may not be notified for the IVDR, which could force some medical device manufacturers to change notified bodies.[1]

Reference

[1] Regulation (EU) 2017/746 on in vitro diagnostic medical devices,

[2] MED DEVICE Online resources page, Marcelo Trevion, MED DEVICE Online web site, 8 Key Changes To Understand In The New European MDR And IVDR. https://www.meddeviceonline.com/doc/key-changes-to-understand-in-the-new-european-mdr-and-ivdr-0001