Claire Ryan, global head of QA/RA, Joanne Cross, director of marketing and Jennifer Golding, product manager at Yourgene Health discuss the in vitro diagnostic regulatory landscape in Europe and how the ongoing changes will help improve the safety of medical devices for patients.
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The in vitro diagnostics (IVD) regulatory landscape in Europe has changed. The European Directive 98/79/EC (IVDD) was in place since 1998 and detailed the control of IVD devices. Since this was a directive, it meant that every member state could implement the guidelines in any way they chose.
Unfortunately, the Directive was quite poorly implemented across EU member states. Around 80% of IVD devices were self-declared under the Directive, meaning that manufacturers were trusted to be able to both create the necessary technical documentation as well as execute a self-determined programme of testing that they deemed appropriate to the risk of the device. This meant that in most cases, manufacturers could declare that the device was entirely safe for use, without any direct external scrutiny.
Why was change necessary?
Regrettably, there were several high-profile scandals surrounding medical devices, in which irresponsible manufacturers’ malpractice in cutting corners showed how easy it was to abuse the Directive. Consequently, the Directive was replaced in 2017 by an EU-wide Regulation, the IVD Regulation (EU) 2017/746 (IVDR), which now applies uniformly across all member states.
The IVDR is a risk-based regulation, with its key objective being patient safety. To underpin this, the IVDR mandates an expanded collection of evidence to be collated by the manufacturer and in many more cases this will now be assessed by a notified body (NB) prior to being placed on the market. NBs are designated by the EU to assess the conformity of the technical documentation to the requirements of the IVDR on behalf of the competent authorities.
There are several big changes to the requirements to gain IVDR compliance:
- The biggest change for manufactures of IVD devices, who were previously in the self-declared space under the IVDD, is a requirement for a significant amount of clinical evidence—far beyond what was required under IVDD. The conformity assessment requirements of the IVDR specify that the manufacturer must provide evidence of scientific validity as well as data demonstrating analytical and clinical performance of the devices.
- There has been a tightening of the way in which a device’s intended purpose may be described. This is the claim which drives the nature of the clinical studies and underpins all of the technical documentation, making it more specific and directed.
- There is also an increase in the level and type of risk management activities within the device development, manufacturing, and marketing processes.
- Obligations have increased with respect to post-market surveillance (PMS) activities. Manufacturers must gather information surrounding all aspects of product manufacturing and end laboratory use, checking that the design is still state-of-the-art, clinically relevant, and fit for the intended purpose. This all must feed back into a manufacturer’s report which proactively goes to the NB on an annual basis.
- Finally, there is now an obligation to register products on a public database, EUDAMED. A summary of safety and performance (SSP), a roadmap to the devices’ technical documentation, must be made available in the public domain until such a time as the EUDAMED database is fully operational.
Classification of Risk
Importantly, the IVDR is a hierarchy-based system in which devices are categorised in four risk groups, labelled A to D, defined by a very specific set of classification rules within the IVDR Annex 8. To summarise, products with the lowest risk, Class A non-sterile devices, comprising around 20% of devices, still fall into the self-declared category (versus around 80% before). However, the technical documentation for these still needs to be of an IVDR standard and available for an NB to audit. This means that even a self-declared Class A product still needs a new set of technical documentation.
For Class A sterile, Class B and Class C devices, the NB will inspect a representative set of technical documentation. How many will depend on the devices’ intended use, the risk of the product and the total number of devices within a manufacturer’s application to an NB. In Class D, all technical documentation for all devices will be reviewed by the NB.
What impact will this have on users?
The IVDR is very prescriptive, it prohibits IVD off-label use, including IVD products used outside of their intended purpose, or prescribed protocol. It also prohibits research-use-only (RUO) products being used for clinical purposes.
Further, it prohibits the use of in-house tests (these may also be referred to as “home-brews” or LDTs, lab-developed tests). Importantly there are some exceptions, or a get-out clause for this prohibition; these are grouped together in a part of the Regulation called Article 5.
For an LDT to claim an exemption against Article 5, no equivalent CE-marked device can be available on the EU market. Any in-house test carried out by an institution must be manufactured and used within a single healthcare institution, no transferring of technology is allowed, and it cannot be set up on more than one site. The in-house test must meet the extensive general safety and performance requirements (GSPR) set out in Annex 1 of the IVDR.
The key message is that the laboratory effectively adopts the role of the manufacturer of the test, and themselves demonstrates and declares compliance with the IVDR, such as Yourgene Health’s Class C DPYD genotyping assay which achieved IVDR certification in 2023. It is no small task to compile this data as the Annex 1 requirements are very significant and effectively include all the things the manufacturer must do including PMS, risk assessment, validation, clinical data collection, plus compiling a set of technical documentation fulfilling GSPR requirements and having a suitably robust and compliant quality management system (QMS) too.
How is the transition going?
Understandably, the transition is already proving to be a cumbersome, arduous and sometimes confusing process to users and some manufacturers alike. A final compounding factor is the scarcity in the number of NBs and their physical capacity to scrutinise the vast swathes of new documentation.
Suffice it to say, we are not at the end of the road yet, especially in light of recent news. Further updates and developments are still expected from the EU Commission in Brussels as they continue to align regulations to ensure patient safety — watch this space!
