The In Vitro Diagnostic Regulation (IVDR) (EU) 2017/746 is the new EU legislation applicable to in vitro diagnostic (IVD) medical devices (shortened to IVDs here for simplicity). IVDR officially entered into force on 25th May 2017 marking the start of a five-year transition period for manufacturers and economic operators, the IVDR replaced the EU In Vitro Diagnostics Directive (IVDD) 98/79/EC. IVDR, in its 157 pages, covers guidance and regulation on established as well as emerging diagnostic technologies, including NGS, AI and others.
As of 26/5/2022, the transition period has run its course. What are some of the major changes?
IVDR introduces stratification of IVDs according to the risk they present, which has been the case with other medical devices in the EU for some time now. All IVDs will be reclassified on a range from class D (high risk) to class A (low risk).
- Class D – High patient risk and high public health risk
- Class C – High patient risk and/or moderate public health risk
- Class B – Moderate patient risk and/or low public health risk
- Class A – Low patient and public health risk
The need for performance and safety evaluation (see below) is tailored for each class and should correspond to the risk the device poses. As part of the new changes, most IVDs that include algorithms will move into ‘higher risk’ classes (B, C and D). For instance, most companion diagnostic products should be clustered in class C.
2. Involvement of Notified Bodies: The transition period is gone, but is it, really?
The strain on Notified Bodies (NBs) to reclassify marketed devices to comply with IVDR is expected to be significant, as many of them now fall in higher risk classes and will require NB involvement. According to some sources, this figure is up to 78% of IVDs under IVDR up from only 8% under IVDD.
Therefore, most devices have been granted prolonged transition periods. Sterile class A and class B devices have the transition period prolonged until the 26th of May 2027, class C until the same date in 2026 and class D devices until the same date in 2025.
Furthermore, another group benefiting from a prolonged transition period are IVDs with an NB involvement under the IVDD. This applies to devices according to Annex II of the IVDD, List A and List B, and for devices for self-testing, regardless of the conformity assessment procedure chosen under the IVDD.
Generally, there are only two types of devices which have not been given the benefit of a prolonged transition period:
· Class A devices that are not labeled as sterile
· New devices for which a declaration of conformity will not be issued until after May 26, 2022
3. Compliance Officer
IVDR explicitly requires companies to appoint a designated role of the "Compliance Officer". Compliance Officer is among other things, responsible for ensuring timely updates of technical documentation, QM conformity checks as well as market surveillance.
He/she must have the following qualifications:
University degree or certificate of completion of a recognized course of study in law, medicine, pharmacy, engineering or another relevant scientific discipline, AND at least one year of professional experience in quality management or regulatory affairs. This professional experience must relate to medical devices.
4 years of professional experience in quality management or regulatory affairs. This professional experience must relate to medical devices.
Compliance Officer must be employed within the manufacturer's organization and cannot be replaced with an external consultant.
4. Direct-to-consumer (DTC) genetic testing is now a fully regulated segment of diagnostics
The FDA in the US had a lot of back and forth over the past years with one of the DTC pioneers; 23andme over whether and how is the company allowed to offer their DNA sequencing services. Meanwhile, in the EU, there was no unified regulation on DTC genetic testing at all. This grey zone was causing concerns for some, especially when it came to so-called "lifestyle tests" their (lack of) interpretation and the need for follow-up counselling. The new IVDR defines DTC testing in the following manner: "genetic testing provided through advertising and selling or (free) provision of genetic tests directly to consumers." and clusters it together under "Devices intended for human genetic testing" under Rule 3i, to be classified as class C IVD devices.
5. Clinical evidence
Depending on the assigned risk classification, manufacturers will need to conduct clinical performance studies to provide evidence of safety and performance. All IVDs will require a performance evaluation report to verify the device’s conformity with the general Safety Performance Requirements (Annex I). Driven by a Performance Evaluation Plan (Annex XIII), performance evaluations must include:
- Intended purpose/intended use
- The analyte or marker
- Target populations
- A description of the state of the art
- How the performance evaluation is to be carried out, including acceptance criteria
- How to determine the acceptability of the benefit-risk ratio
This information is structured as a Performance Evaluation Report (PER) which is a body of data used as the clinical evidence needed to conform to the IVDR requirements. Conforming might not mean simply "passing" the assessment by an NB. The PER must be updated throughout the life cycle of the IVD product with new data obtained from post-market performance follow-up (PMPF) and systematic post-market surveillance (PMS). For higher-risk classes C and D, PMPF and PMS shall be updated on an annual basis.