Potential Impacts of EU IVD-Regulation on the Clinical Flow Cytometry Lab
Maurizio Suppo, PhD
Like many other ideas that are intended to improve existing products or procedures, the new European IVD Regulation (IVD-R) 2017/746 road is paved with good intentions. However, some of these intentions may potentially render the daily life of clinical flow cytometry laboratories a lot more complex than what they are now, due to the latest regulations for Laboratory-Developed Tests (LDTs).
Transition period for IVD-R
The legislative tefit still used to regulate the distribution of all IVDs in Europe is the old IVD Directive 98/79/EC, which was drafted almost 25 years ago and, as with anything old, started to show some severe limitations due to its age – particularly when compared with other IVD legislations in different parts of the world.
A few signs of age of the current IVD-Directive are the fact that companion diagnostic, tumor marker and even the recent COVID-19 (RNA or serological) assays are all in the self-certifcation class and can be placed on the EU market solely under the exclusive responsibility of their manufacturers without the intervention, supervision and approval of any third party (Notified Bodies).
Aware of the limitations of the existing IVD-Directive, the regulators who wrote the IVD-Regulation (a mix of EU Commission with interventions by the EU Parliament and Council) set the bar very high – in particular for IVDs – and thus, published a new regulation that in terms of complexity and cost, can stand shoulder-to-shoulder with other existing regulatory tefit and/or content.
In May of 2017, when the EU Commission published the two new legislative tefits that will regulate both medical devices (2017/745 MD-R) and IVDs (2017/746 IVD-R) going forward, the transition period that began allowed an IVD manufacturer to place a product on the EU market under the IVD-Regulation; the fact that no one did it up to now maybe due to several reasons among which the most notable are:
- The first couple of IVD-R Notified Bodies (NBs) started to appear only in October 2019 and, up to now, there has been little progress with the name of another one. The UK one should not be counted due to the fact that with Brexit finally happening it will lose its status as of January 1, 2021. In fact, all the focus has been on the nomination of Medical Device-Regulation (MD-R) NBs and then COVID-19 hit the world, and everything stopped. Without NBs, manufacturers cannot have their devices approved as per the IVD-R.
- Launching the first device on the market under the IVD-R implies having all those processes in place for performance evaluation and post-market surveillance, and this is no small task to accomplish.
In its review of the former and new legislative tefits, this article will provide a high-level broad coverage of the new EU IVD Regulation and will specifically elaborate on how the EU authorities will regulate the vast majority of the Laboratory-Developed Tests (LDTs), which are currently done in Europe on a daily basis.
IVD-Directive changes to come
Looking to the new year through the lens of the new IVD-Directive, the top four things that will bring about change are:
- Massive involvement of Notified Bodies on all tests detecting/measuring something.
- Much higher expectations on how manufacturers demonstrate clinical evidence for their devices.
- A concept of performance evaluation for the IVD devices, which includes a much reinforced and more sophisticated approach to Post-Market Surveillance.
- A different approach to Laboratory-Developed Tests (LDTs).
1. Notified Bodies everywhere
All qualitative or quantitative tests fall within the scope of the Notified Body that the manufacturer will have to choose, pay and work with. Considering that around 90 percent of the IVD assays in circulation today do fall in the IVD-Directive self-certification class (no involvement of a Notified Body), this truly represents a revolution for several IVD manufacturers; a paradigm shift.
All those IVD manufacturers that were making assays in the clinical chemistry, endocrinology, allergy, tumor markers and even companion diagnostics will find themselves forced to come to terms with thorough and challenging Notified Body reviewers and will have to convince them that their quality management system is good. This includes that they are properly managing suppliers and, in particular, contract manufacturers, that their design control, performance evaluation and post-market surveillance processes are yawless, and that their assay-specific technical documentation is well structured, complete and has all the I’s dotted and the T’s crossed.
We start to have the first glimpse of the new audit and TD review fees of the IVD-R NBs and they are very high, as it could be expected considering that we will likely have a third (or a little more) of the number of NBs we have today for the IVD-Directive (much fewer competitors) and an explosion of work (85 percent of IVDs will require NB involvement and approval under the IVD-Regulation vs only 15 percent under the Directive). A major NB (already nominated for the IVD-R) estimated this at a 600 percent increase in workload with respect to the one related to the IVD-Directive.
2. Higher bar on clinical evidence
Manufacturers will have to work harder to prove that their device is worth approval from the NB. In the past (under the Directive framework), NBs were involved only on few IVDs (those listed in Annex II A, B and self-tests) and even for those the NBs were essentially focusing on the analytical performance. Now, under the IVD Regulation, the focus on clinical evidence has broadened the work required, forcing manufacturers to demonstrate also the scientific validity (the link between the analyte and the clinical condition) and the clinical performance in addition to the analytical performance. This focus is new for many manufacturers and will imply a lot of work and considerable costs.
3. Performance evaluation at 360°
If you believe that performance evaluation is what you have to do before you launch the product on the market, you have not understood the spirit of the IVD-Regulation.
Performance evaluation is a “cradle to grave” process that must continue well beyond the product launch and has to last until product discontinuation. No performance evaluation plan is complete unless it includes a well thought out and rather elaborate post-market surveillance plan. And such a plan must include the assessment on whether Post-Market Performance Follow-up studies (PMPF) aimed to continuously reassess how the device in question performs when compared with the other similar products. The formal documentation of state-of-the-art or competitor landscape evaluation, another new concept, has become an obligation under the IVD-R.
The three points above do represent a massive change for IVD manufacturers. A paradigm shift that:
a) Will leave several products on the ground because they will not be “IVD-Rized” due to the cost of filling the gaps and perhaps due to the fact that they have reached the end of their expected life-cycle, and
b) Will probably leave some companies on the ground because they will not be able to rise to the much higher bar imposed by the IVD-R.
These two factors are likely to change the shape of the EU IVD market with possible effects going well beyond the EU.
4. The LDT nuclear bomb
However, there is a fourth element of change that will primarily impact clinical laboratories and not only within the EU. It will also affect IVD manufacturers. And this just by itself is a potential nuclear bomb that, if enforced correctly, will shake-up the world of IVD testing.
The LDT nuclear bomb
Very few people seem to have realized that the regulators who wrote the IVD-R dropped a nuclear bomb on LDTs.
They used the classic “two-punch” boxing technique first by writing Art. 5.1: “A device may be placed on the market or put into service only if it complies with this Regulation when duly supplied and properly installed, maintained and used in accordance with its intended purpose.”
Art. 5.1 seems innocuous because it simply states that devices that are placed on the (EU) market have to comply with the Regulation. However, the other punch is delivered with Art. 5.4, which without mentioning them directly, essentially states that all LDTs are considered as placed on the market: “Devices that are manufactured and used within health institutions (…) shall be considered as having been put into service.”
The two together (Art. 5.1 + 5.4) equal to the statement: “all LDTs have to comply with the IVD-Regulation.”
The spirit of Article 5.5
Art. 5.5 further elaborates on this by providing very few exceptions for LDTs to be outside the scope of the IVD-Regulation. The spirit of Art. 5.5 is that true European Health Institutions (see later definition) shall be allowed to make their own LDTs where there are no commercially available products. This would protect the labs to develop in full freedom LDTs for rare diseases for which no industrial IVD manufacturer bothers to make an assay, or for those emerging diseases (think about the recent COVID-19 situation) for which industry has not yet developed commercially available tests.
However, the limitations imposed by Art. 5.5 are very thorough and they are summarized below:
To develop, manufacture and use an LDT a lab must fulxll all of these requirements:
- Be a European health institution
- The IVD-R gives a definition in Art. 2 (29): “Health Institution means an organization the primary purpose of which is the care or treatment of patients or the promotion of public health.” Although a definition is given, we still think that it is subject to interpretation and will need to be further clarified. For example, it is not entirely clear whether an EU private lab contracted to do IVD tests on behalf of the national healthcare service can be considered as a health institution or not. For sure, any non-EU lab will not fit the definition and therefore cannot do LDTs on EU citizen samples being shipped to them.
- Comply with the General Safety and Performance Requirements (GSPR) listed in Annex I of the IVD-R.
- This is no small feat. Complying with the GSPR listed in Annex I of the IVD-R is hard work and involves extensive test and documentation.
- Have an appropriate Quality Management System (QMS)
- The European Health Institution lab is required (in order to do its own LDTs) to have a QMS system in place and the IVD-R even goes on to specify that it shall be compliant with the ISO-15189 “Medical laboratories — Requirements for quality and competence,” which is for a clinical laboratory what ISO 13485 is for an IVD manufacturer. Actually the 15189 is even harder because in addition to the requirement for a QMS that covers all the diagnostic phases (pre-analytical, analytical and post-analytical) it requires the lab to get accredited for each single measurement/analysis they do.
- The IVD-R also recognizes that there are some countries (France is just one example) where there are national accreditation schemes for clinical laboratories that are equal or even harder than 15189.
- The EU Health Institution commits not to distribute their own LDT to other legal entities (other laboratories that belong to different hospitals).
- The EU Health Institution has to justify that the specific (diagnostic) needs of the target population cannot be satisfied by an equivalent test available on the market.
- The current interpretation of this is that if there is an IVD manufacturer with an IVD-CE-marked assay that fulfills the testing needs of the lab, then such lab cannot do its own LDT and has to buy the IVD-CE-marked assay.
Who will be responsible for the enforcement of these above conditions? For monitoring what clinical laboratories will do? The Health Authorities of the country in which the laboratory is located. Some Health Authorities of a few European countries have already commented that they are fully aware of the enforcement obligations which will be triggered by Art. 5 of the IVD-R and they are actively preparing for it. Others have not commented, so it is not possible to know whether they are preparing for it or not.
The nuclear fallout of Art. 5 described above will reach far. Laboratories that today routinely provide patient-related diagnostic information using LDT technologies (like flow cytometry labs or labs using HPLC and mass spectrometry technology – just to list two examples) will be fully impacted by Art. 5 and its several points.
Few labs of those EU-based Health Institutions will be able to do some LDTs but, practically speaking, only for those rare diagnostic tests which are not in any IVD manufacturer catalog. And even then, the conditions they will have to fulfill will be very heavy.
For the rest of the labs, which represent the vast majority of the clinical labs, it won’t be possible to do LDTs in Europe, or they won’t be able to do LDTs outside Europe on specimens from European citizens living in Europe which are shipped to them. Stepping up to the requirements of the IVD-R listed in the points above will be, frankly speaking, too difficult for such labs. The only alternative solution is for the IVD-industry to rise to the challenge and transform all these current non-IVD CE-marked technologies into ones fully compliant with the IVD-Regulation.