With the newly EU IVDR just published and with the US FDA interpretation on current legislation maturing, it is time to reflect on the direction authorities are taking towards genetic testing. On first review, it is clear that there will continue to be significant differences between FDA’s application of US laws and regulations and those of the EU in vitro Diagnostics Regulation (EU 2017/746). Let’s look at recent notices from FDA regarding proposed exemptions from premarket notification [510(k)] of genetic health risk assessment systems and autosomal recessive carrier screening gene mutation detection systems.
FDA added 21 CFR 866.5950 and has proposed exempting devices of this type from 510(k). The generic type of device is named genetic health risk assessment system, and it is identified as a qualitative in vitro molecular diagnostic system used for detecting variants in genomic deoxyribonucleic acid (DNA) isolated from human specimens that will provide information to users about their genetic risk of developing a disease to inform lifestyle choices and/or conversations with a health care professional. This assessment system is for over-the-counter use. This device does not determine the person’s overall risk of developing a disease.
Similarly, FDA exempted from 510(k) the autosomal recessive carrier screening gene mutation detection systems (e.g. Bloom disease), 21 CFR 866.5940. This type of device is a qualitative in vitro molecular diagnostic system used for genotyping of clinically relevant variants in genomic DNA isolated from human specimens intended for prescription use or over-the-counter (OTC) use. The device is intended for autosomal recessive disease carrier screening in adults of reproductive age. The device is not intended for copy number variation, cytogenetic, or biochemical testing
Noteworthy for both of these device types, is not only the 510(k) exemptions, but also the intended use of over-the-counter.
So, how does this stack up under the EU IVDR, EU 2017/746 that entered into force in May 2017?
The IVDR does not recognize the term “over the counter” but instead defines a device for self-testing in Article 2 (5) to mean any device intended by the manufacturer to be used by lay persons, including devices used for testing services offered to lay persons by means of information society services. Devices for self-testing are mostly Class C (Annex VIII, Rule 4), as is genetic testing (Rule 3), to which both genetic health risk assessment assays and autosomal recessive carrier screening gene mutation detection systems are applied. Thus, the conformity assessment procedure (Article 48) is the same none the less. However, the self-testing claim does bring with it specific requirements listed throughout the IVDR, particularly with labeling as specified in Annex I (General Safety and Performance Requirements).
Although the IVDR gives the opportunity to select from a series of conformity assessment routes, most manufacturers will likely elect conformity assessment procedure as specified in Chapters I and III of Annex IX (Conformity Assessment Based on a Quality Management Systems and on Assessment of Technical Documentation-Quality Management System), including an assessment of the technical documentation as specified in Sections 4.4 to 4.8 of that same Annex of at least one representative device per generic device group. In other words, a full quality system approach, inclusive of the design and development process, supported by a documentation review based on sampling.
What this means from a practical point, is that although the US plans to exempt these devices from FDA review, the design and development work must still occur and be filed internally, but time is saved not having to go through the FDA review cycle. Design and development will also be performed and documented for placing on the EU market, however prior to placing on the EU market, the Notified Body, besides performing audits, will have to review the technical documentation and issue a CE certificate. This is the complete opposite of life under the current IVD Directive, where notified body involvement towards self-tests are only related to the correct understanding of labeling and IFU by lay people. The longer lead times to market will in the near future be for the EU markets rather than US under the IVDR for these 2 examples and likely be the same for many others.
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