Part 1.
Overview of regulatory framework, its applicability and transitional provisions
As of May 26, 2022, the new Regulation on In-vitro Diagnostic Medical Devices (EU) 2017/746 ("IVDR") becomes fully applicable and provides the new regulatory framework for in-vitro diagnostic medical devices ("IVDs"), from performance evaluation and performance studies, to placing on the market, making available, putting into service and the surveillance of IVDs on the European Union (“EU”) market.
1. The Legal Form of a Regulation
The IVDR replaces the former EU Directive on in-vitro diagnostic medical devices of 1998 (Directive 98/79/EC - "IVDD"). The fact that the IVDR will entail extensive changes and conversions for all areas of the IVD market and thus not only editorial changes is already evident from its level of detail: With 113 articles and 15 annexes, its scope of provisions has almost increased fivefold compared to the IVDD (with 24 articles and ten annexes).
- As a EU-regulation, the IVDR is directly applicable in all Member States and therefore does not require any further transformation into national laws. However, further specifications in all Member States are nonetheless necessary, on the one hand with regard to mere national aspects such as the competence of the (regulatory or supervising) authorities, the participation of Ethics Committees in the authorisation procedure for performance studies, criminal prosecution and provisions on fines, and on the other hand in case of so-called opening clauses which the EU Commission has foreseen in the IVDR and left to the Member States for stricter national provisions. In Germany, the regulatory framework of the IVDR is therefore supplemented to a large extent by the new Medical Device Implementation Act (“Medizinprodukterecht-Durchführungsgesetz” – MPDG).
2. The main characteristics of the IVDR at a glance
The objectives envisaged by the IVDR are mainly to harmonise the requirements applicable to the IVD industry in the EU, to ensure a high level of safety and health protection, but also to create fair market access also for small and medium sized companies operating in this sector. In order to improve public health and safety of patients and IVD applicants alike, core elements of the current regulatory approach (inter alia the oversight of Notified Bodies, risk classification, conformity assessment procedures, performance studies and assessment, vigilance and market surveillance) will be significantly strengthened and provisions to ensure transparency and traceability of IVDs introduced:
- New system for classification: In order to improve patient safety and with due regard to technological progress, the former list system of the IVDD has been repealed by new, risk-based classification rules now established in the IVDR. Considering the intended purpose and the associated risks, IVDs will henceforth be classified into classes A, B, C and D and in accordance with the classification rules detailed in Annex VIII of the IVDR. Products with only a low risk are assigned to class A (e.g. washing solutions) and with increasing risk for patients and public health up to class D (e.g. IVDs for the determination of life-critical and highly infectious diseases) as the highest risk class. Companion diagnostics (CDx), which are explicitly regulated under the IVDR for the first time, are classified as class C IVD.
- Conformity assessment procedure: Prior to placing its IVD on the market, a manufacturer must undergo a procedure to assess the conformity of the respective products with the requirements of the IVDR. Only after a successful completion of the conformity assessment procedure will the manufacturer be allowed to affix a CE mark to its product and issue a declaration of conformity. Depending on the risk class, the manufacturer has a choice between different conformity assessment procedures. For class A IVDs (non-sterile), the manufacturer can declare the conformity of the devices under its sole responsibility. For IVDs of classes A (sterile), B, C and D, to which the majority of devices on the market will be assigned to, conformity assessment can only be carried out by the manufacturer with the involvement of a Notified Body. The essential novelty compared to the IVDD is to be seen in the reduction of the available conformity assessment procedures to three and thus
- assessment of the Technical Documentation and the Technical Documentation on post-market surveillance only (Annexes II and III of the IVDR),
- conformity assessment based on the quality management system and the assessment of the technical documentation (Annex IX of the IVDR), or
- conformity assessment based on type-examination (Annex X of the IVDR).
In addition, the conformity assessment procedure for risk class D IVDs requires the involvement of European reference laboratories for compliance with relevant specifications and performance of the IVD.
- Increased regulatory obligations for manufacturers: The manufacturer is - as was already the case under the IVDD - the main addressee of regulatory obligations under the IVDR. However, the requirements for the quality management system, the preparation and updating of the Technical Documentation and the post-market surveillance have increased significantly. In addition, manufacturers must appoint at least one person in their organisation who is responsible for compliance with the new requirements of the IVDR (person responsible for regulatory compliance - PRRC). This person's professional qualification must be proven by the manufacturer. Micro and small enterprises are not exempt from this obligation; however, the IVDR provides them with the option of relying on an external PRRC.
- Regulating other economic operators: The main objective of the IVDR is the complete traceability of all IVDs on the EU market. Therefore, clear regulatory obligations are laid down not only for manufacturers, but also for the authorised representative, the importer and every distributor as an economic operator involved in the distribution of the products. The IVDR does not only impose verification obligations on economic operators before placing and making the products available on the market, but also require close interaction with manufacturers and regulatory authorities throughout the whole distribution process – up to ensuring that all necessary corrective actions are taken to bring IVDs concerned into conformity, to withdraw them from the market or to recall them, if necessary.
- (New) Regulations on lab-developed tests and companion diagnostics: The scope of the IVDR is significantly expanded and provides regulations for certain product groups: Companion diagnostics (CDx) are defined by law for the first time and their use in performance studies as well as special aspects of the conformity assessment procedure are specified. There are also far-reaching regulations with regard to the use of so-called lab-developed tests ("LDTs"), i.e. IVDs that are developed, manufactured and used within one healthcare facility and are thus not sold to third parties. Although the IVDR still allows the manufacture and use of LDTs for which the healthcare facility can demonstrate conformity with the essential safety and performance requirements set out in Annex I of the IVDR, without the involvement of a Notified Body and without CE marking of the devices concerned. However, their use as LDTs is now only permitted to healthcare facilities - and this is the essential change - if no CE-marked IVD is available on the market that can satisfy the specific requirements of the patient population or can satisfy them at the indicated level of performance.
- Detailed provisions on the authorisation and conduct of performance studies with IVDs: The IVDR sets much higher requirements for the performance evaluation of IVDs and the conduct of performance studies. The core of formal procedural innovations is the submission of the application documents necessary for the approval of a performance study via an electronic portal (EUDAMED, see below), which serves as a communication platform for all stakeholders involved in the study (sponsors, authorities and Ethics Committees alike). In case of multinational performance studies, the sponsor is thus spared an unnecessary, resource-consuming multiple submission of essentially identical application documents. Whether a full approval procedure or only an application procedure is required (and thus whether the study can already be started if the competent authority has not objected within a short period of time) depends on the regulatory classification of the performance study based on an assessment of associated risks for the trial subjects. The substantive provisions on the protection of study subjects have also been extensively amended, which, in addition to detailed provisions on informed consent, the need for a risk-benefit assessment, the obligation to take out insurance, etc., also impose special requirements on the inclusion of minors, adults who are incapable of giving consent, pregnant and breastfeeding women.
- New requirements for Notified Bodies and market surveillance: The IVDR standardises an extensive catalogue of criteria that conformity assessment bodies must fulfil for their designation as a Notified Body under the IVDR and undergo a designation and notification procedure. Furthermore, not only are Notified Bodies themselves subject to continuous regulatory supervision, but they must also undergo a full reassessment (initially three years after notification and every four years thereafter) to ensure that the Notified Body still meets the requirements imposed on it. In addition, the IVDR strengthens the position of Notified Bodies vis-à-vis manufacturers and grants them further rights (and obligations), including to carry out unannounced on-site audits of manufacturers and also suppliers and to carry out physical inspections or laboratory tests on IVDs. They will be required to ensure that manufacturers comply with the provisions of the IVDR at all times, even after initial certification.
- Post-market surveillance and vigilance: For each IVD that a manufacturer places on the EU market, the manufacturer is required to plan, establish, document, implement and, when necessary, update and adapt a post-market surveillance system appropriate to the risk class of the device. This system is an integral part of the manufacturer's quality management system and obliges the manufacturer to actively and systematically collect and evaluate all data on the quality and safety of its marketed IVDs, on the basis of which any preventive or even corrective measures have to be identified and implemented. The IVDR also requires manufacturers to record these monitoring activities in a continuously updated report that must be disclosed to Notified Bodies and regulatory authorities. For IVDs assigned to risk classes C and D, this report must be updated at least annually. The manufacturer's vigilance obligations have also been detailed and cover serious incident reports, field safety corrective actions and trends (statistically significant increase in the frequency or severity of non-serious incidents).
- EUDAMED: An important element of the IVDR is the new European database EUDAMED (European Database on Medical Devices), which was set up with the aim of creating more transparency, bundling information in a targeted manner and serving as an exchange and reporting platform for all economic operators, Notified Bodies and competent authorities. EUDAMED, the contents of which are partly publicly accessible, is composed of the following six modules: (1) registration of economic operators, (2) unique device identifier (UDI) and device registration; (3) certificates and Notified Bodies; (4) clinical investigations with medical devices and performance studies with IVDs; (5) vigilance and post-market surveillance, and (6) market surveillance.
- UDI: By introducing the Unique Device Identification system, the traceability of products within the supply chain shall be simplified and a faster recall of IVDs by the manufacturer shall be made feasible.
3. Transitional provisions of the IVDR
Since 26 May 2022, all in-vitro diagnostic medical devices to be placed on the EU market must comply with the new regulatory requirements of the IVDR. However, provided certain conditions are met, manufacturers can benefit from the transitional provisions of the IVDR, which are as follows:
- IVD with certificate issued under the IVDD by a Notified Body
- If a certificate was issued for the respective IVD by a Notified Body before the entry into force of the IVDR on May 26, 2017 in accordance with the IVDD, these certificates shall remain valid until the expiry date specified therein, except in the case of certificates in accordance with Annex VI of the IVDD, which shall cease to be valid on May 27, 2025 at the latest.
- If a certificate was issued by a Notified Body in accordance with the IVDD after May 25, 2017, the certificate will lose its validity by May 27, 2025 at the latest.
- IVDs for which the manufacturer (a) issued the declaration of conformity under IVDD before 26 May 2022 and (b) require the involvement of a Notified Body in the conformity assessment procedure under IVDR may continue to be placed on the market as follows:
- until May 26, 2025, if IVD falls under class D under the IVDR;
- until May 26, 2026, if IVD falls under class C under the IVDR;
- until May 26, 2027, if IVD falls under class B or class A (sterile) under the IVDR.
However, the placing on the market of devices under the aforementioned transitional provisions requires that the IVDs continue to comply with the requirements of the IVDD and that the manufacturer has not made any significant changes to the layout/design and medical purpose of the devices. Furthermore, the aforementioned transitional provisions do not apply
- to IVDs which are also assigned to risk class A (non-sterile) under the IVDR and for which the manufacturer can declare conformity itself under the IVDR without the involvement of a Notified Body; and
- to "new" devices for which the manufacturer declares conformity only after the full application of the IVDR on May 26, 2022.
Furthermore, it should be noted that the aforementioned transition periods do not apply to the obligations for registration, post-market surveillance, vigilance and market surveillance. In this respect, IVDR compliance is already required since May 26, 2022.
