On May 26, 2017, the new Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices (In-vitro-Diagnostic Device Regulation, IVDR) entered into force. It replaces the current EU directive on in vitro diagnostic medical devices (98/79/EC) and the decision 2010/227/EU.
The aim of the new IVDR is to set high safety standards for in vitro diagnostics. It intensifies the conformity assessment and risk classification, describes performance assessments and performance studies and requires post-market surveillance, vigilance, transparency and traceability of in vitro diagnostics.
We summarise how this new regulation affects you.
What are the changes?
The new IVDR increases the responsibility of manufacturers for the clinical use of their products. Higher requirements for diagnostic development, such as evidence of clinical benefit and performance studies, are the new challenges. A distinction is drawn between three areas:
- Analytical validation: Evidence that the correct analyte is measured.
- Clinical validation: Evidence that the measured biomarker is meaningful for the particular disease.
- Clinical utility: Proven benefit for the patient.
New products will be certified once these three points have been proven.
The new regulation also introduces vigilance. Thus, even after its certification a product must be validated within regular intervals to ensure its quality. To validate diagnostic test systems, human biospecimens are needed.
From the extent of the new IVDR you see how extensive the changes are: while the old directive had only 24 paragraphs, the new regulation covers 113. The number of pages has also increased from 47 to 476 pages. After a transition period of 5 years for already certified in vitro diagnostic medical devices (May 26, 2022) and a ‘warehouse clause’ of additional 3 years for sales, 2025 will be the definite date of validity.
Extent of the IVD Directive 98/79/EC compared to the IVD Regulation 2012/0267.
What are the consequences?
- Obviously, the number of test procedures will increase. Previously, in vitro diagnostics had to be tested only for the certification. From now on there must be frequent tests ensuring correct functionality during the entire life cycle of the product.
- The establishment of quality management procedures also requires more testing.
- At the same time, there may be fewer Notified Bodies conducting conformity assessments (see paragraph "New tasks for the Notified Bodies"). This might lead to delays.
It is therefore particularly important to submit flawless test results and a complete technical documentation to the Notified Bodies to avoid unnecessary delay of the testing procedures.
The increasing number of tests will require more human sample material in the future. Considering that in the new IVDR the samples used for validation are an integral part of the documentation, detailed information on collection, storage, analysis and the donor is essential.
The procurement of qualified human specimens, which are ethically and legally sound, is therefore becoming increasingly important. High-quality human sample material minimizes risks and ultimately saves time.
How can Central BioHub help?
The extensive changes and the frequent product validations increase the need for human biospecimens and the importance of fast and reliable delivery of high quality biospecimens.
Central BioHub has a supplier-independent validation and auditing system to ensure the high quality of the samples. You see all specifications for the sample material at a glance, such as preanalytics, storage conditions, parameter analysis, donor-related information and clinical course aspects. Specific disclaimers for the application areas ensure the correct use according to your compliance regulations.
All samples found on the website are in stock and will be shipped within a few days. So there is no time loss due to long request and waiting times.
The ethical and legal aspects have the highest priority and are presented transparently.
We support you in your Research & Development project and are happy to advise you on the new requirements that await your company.
Why were these changes necessary?
The IVDR has been amended as part of the revision of the Medical Devices Directive (MDR). The new regulation aims to protect both users and patients as well as the internal market from low-grade products and the resulting dangers. In vitro diagnostics are rated much stricter than before.
The goal is to adapt the IVDR to the MDR, especially regarding the introduction of risk-based classification rules, but also the traceability of products and supply chains as well as the obligation to provide clinical evidence. Norms and standards are internationally harmonized to avoid legal uncertainties: the previous Directive 98/79/EC was interpreted differently in the Member States, so that there were no uniform safety standards for in vitro diagnostics. The new regulation, on the other hand, does not require national implementation, thereby reducing national regulations. Thus, free movement of goods and a high level of security should be ensured at the same time.
Who is affected?
The IVDR covers all manufacturers (IVDR § 10), importers (IVDR § 13) and distributors (IVDR § 14) of in vitro diagnostic medical devices. In some cases the rules for distributors also apply to importers (IVDR § 16). All stakeholders must ensure the traceability of the supply chain (IVDR § 22.1). In addition, a comprehensive internal quality management and risk management system (IVDR § 10.8 and § 10.2) must be established in order to comply with the requirements of the regulation.
Existing certificates are valid for another two years, as long as the products are not changed and are monitored by a Notified Body.
The regulation does not apply to in-house products (IVDR § 5.5), as long as they meet strict requirements (including ISO standards).
What are the specific changes?
The main changes comprise three areas: risk classification, conformity assessment and transparency.
Stricter risk classification - categorization by purpose
The new regulation results in a much stricter risk classification by a Notified Body based on the intended use. The new risk classification eliminates self-classification.
From now on, a distinction is made between the risk classes A, B, C, and D (IVDR § 47.1, according to Annex VIII). You can find rules for the classification of in vitro diagnostic medical devices by purpose in Annex VIII of the Regulation. If an in vitro diagnostic medical device is intended for a number of intended uses, it will be assigned to the higher risk class. If the product is a combination of several in vitro diagnostic medical devices, the components are classified individually.
Depending on the class the Notified Bodies will chose the conformity assessment procedure and award the CE certificate, as soon as conformity is confirmed.
- Risk class A
- This class contains general laboratory supplies & accessory (buffer solutions, washing solutions, general nutrient media, histological stains, etc.), as well as specimen receptacles and instruments.
- For these products the manufacturer's declaration of conformity is still sufficient (IVDR § 48.10).
- Risk class B
- This class is a collecting group for all in vitro diagnostics that do not fit in the remaining risk classes, such as control devices, devices intended for self-testing (such as urine tests for the detection of glucose, erythrocytes, leukocytes and bacteria), as well as in vitro diagnostics for detection of cholesterol, pregnancy and fertility testing.
- The conformity assessment is based on clinical performance studies, the manufacturer's quality management and technical documentation, but only for a representative product per product category (IVDR § 48.9).
- Risk class C
- In this group are tests for the detection of sexually transmitted and contagious diseases without high risk of propagation, companion diagnostics, genetic testing, blood typing tests (except those in risk class D), tissue typing and devices intended for self-testing (with the exception of products in risk class B).
- Conformity assessment is based on clinical performance studies, the manufacturer's quality management and technical documentation for at least one representative product per generic product group (IVDR § 48.7).
- Risk class D
- This group contains in vitro diagnostic medical devices for the detection of infectious diseases with high risk of propagation, as well as tests for the determination of the degree of infection of life-threatening diseases and tests for blood typing or tissue typing according to specific markers (Annex VIII, 2.2).
- The conformity assessment is carried out according to Chapter I, Chapter II (excluding Section 5) and Chapter III of Annex IX of the IVDR.
- For near-patient tests the manufacturer must also follow additional procedures for the assessment of the technical documentation (IVDR§ 48.3, in accordance with Annex IX 5.1).
While previously only class D products have been tested, conformance testing for in vitro diagnostics for the classes B and C are also required now.
New is that accessories now count as in vitro diagnostic medical devices, as long as their purpose is exclusively related to in vitro diagnostics.
Software, calibrators and control materials receive the class of the product they are designed to control or influence.
Stricter conformity assessment procedures - performance evaluation as an ongoing process
Depending on the risk class, different measures for conformity assessments are necessary.
The manufacturer is obliged
- to perform performance studies and performance assessments prior to admission (IVDR § 10.3),
- to establish a quality management system (IVDR § 10.8) that includes risk management (§ 10.8e).
- to record all measures in a detailed technical documentation (IVDR § 10.4).
The real innovation, however, concerns the monitoring of the product after its commercial launch (IVDR § 10.3).
- The performance evaluation for in vitro diagnostics is now an ongoing process (IVDR § 56, Annex I & Appendix XIII).
- The performance evaluation of the products in the risk classes C and D has to be updated at least once a year during their entire life cycle (IVDR § 56.6).
- This also applies to the conformity assessment bodies. They monitor the certification even after the approval and regularly check, whether the product still meets the requirements.
After approval, the certificate of conformity is valid for max. 5 years and can be renewed for another 5 years (IVDR § 51).
In addition, reference laboratories designated by the EU will carry out random checks on the products of class C and D in the future (valid 18 months after the date of application, 26.11.2023) (IVDR § 100).
Transparency - traceability system
The new IVDR plans to establish a European database for medical devices (EUDAMED) by 2022. Within the EUDAMED there will be a system, which allows easy traceability of each product.
- The Unique Device Identification System (UDI system) (IVDR § 25) is intended to create transparency by assigning a unique product identifier to each product (IVDR § 24.1, Annex VI) and registering it digitally in the EUDAMED system.
- These labels are recorded in the declaration of conformity (IVDR § 24.6) and in the technical documentation (IVDR § 24.7).
- Manufacturers and importers of in vitro diagnostic medical devices receive unique identification numbers as well (IVDR § 28.1, Annex VI Part A).
Traceability with the UDI system ensures a close control of the supply chain. In addition to the traceability of individual products and the clear identification of the manufacturer there is an increased liability (IVDR § 10.15). Accordingly, the manufacturers or their authorized representatives assume liability for any damage caused by their product.
The long-term goal is to provide security and comparable information in the database and the product register (IVDR § 101).
How do the changes affect you?
Overall, there is a significant tightening of controls. It does not change the test procedures, but the frequency of testing. How often a product is audited by the Notified Bodies depends on the risk class (see paragraph "Stricter risk classification - categorization by purpose") (IVDR § 48.13).
In addition, there will be random announced and unannounced inspections (IVDR § 88) by the competent authority.
EUDAMED will contain all information such as safety reports and inspection reports for the conformity assessment (IVDR § 87) as well as information on nonconformity. The database is supposed to facilitate the communication between Notified Bodies, competent authorities and manufacturers (IVDR § 30.2).
Changes for manufacturers
Manufacturers are encouraged to act proactive.
- The manufacturer is obliged to check the effectiveness of the product during its entire life cycle (IVDR § 10.3 and 10.9).
- Manufacturers of in vitro diagnostic medical devices of risk classes A and B must submit a report on the surveillance (IVDR § 80).
- For products of the risk classes C and D a safety report must be compiled at least once a year as part of the technical documentation (IVDR § 81).
- For in vitro diagnostic of class D the safety report must be provided by the manufacturer via the EUDAMED electronic system (IVDR § 81.2).
- For class C products the safety report must be provided only during the conformity assessment (IVDR § 81.3).
- If nonconformity is detected, the manufacturer must restore conformity within a specified period, otherwise the product will be withdrawn from the market (IVDR § 92) until effective corrective measures have been taken (IVDR § 94.3).
- Performance studies are subject to an ethical review by the Ethics Committee (IVDR § 58.3) and will be digitally recorded for information exchange (IVDR § 66).
- In addition, the manufacturer reports trends or statistically significant frequencies to the competent authorities via the EUDAMED electronic system (IVDR § 83). Thus, it is possible to detect accumulations of diseases at an early stage.
Overall, the rules for conducting performance assessments and clinical performance studies are becoming more rigorous, as it is indicated by increased mandatory information, such as exact sample data (IVDR Annex II, 126.96.36.199 and Annex XIII).
So the documentation will be more detailed. For the validation of a product you will need a precise description of the sample types as well as exact information on storage conditions and cross-reactions by other substances in the sample, such as drugs or food (IVDR Annex II). Finally there also is the post-market surveillance by the manufacturer (IVDR Annex III).
New tasks for the Notified Bodies
For conformity assessment bodies it will be much more difficult in the future to obtain the status of a Notified Body. They either submit an application to the competent authority (IVDR § 34) or they are designated by the EU member state (IVDR § 38). Already existing Notified Bodies according to IVDD 98/79/EC have to be reassessed.
The following new areas of responsibility apply to the Notified Bodies.
- They evaluate the quality management systems of the manufacturer.
- The conformity assessment procedures now include regular on-the-spot checks at the manufacturer's premises.
- The Notified Bodies will perform unannounced tests in addition to the monitoring and interim audits. It will be checked whether the product complies with the technical documentation and the legal requirements as well as the traceability.
Notified Bodies themselves will be monitored more closely in the future.
- Notified Bodies are controlled by the competent authority (IVDR § 21.1) and must always provide their documents (IVDR § 40.2).
- At least once a year the competent authority checks whether the Notified Body still fulfills the requirements (IVDR Annex VII) (IVDR § 40.4). This also happens through unannounced audits (IVDR § 40.7).
- Every 4 years there is a complete reassessment of the Notified Body regarding the requirements from IVDR Annex VII (IVDR § 40.10). Especially the test procedures of the Notified Body (IVDR § 41) will be checked.
- If a Notified Body terminates the conformity assessment, the certificates issued by it are still valid for 9 months, as long as another Notified Body confirms it (IVDR § 42.9).