EU IVD Regulation – What does it mean for companion diagnostics and LDTs?

Dave Smart

Dave Smart, PhD, Director at Diaceutics, discusses the introduction of the EU IVD Regulation. While it is considered a necessary step, the Regulation raises issues not only for labs and those manufacturing companion diagnostic and laboratory developed tests, but also for pharma, all of whom need to be aware of potential grey areas where more clarity is needed.

The new European Union (EU) In Vitro Devices Regulation (IVDR) has entered member states legislation and will come into full force in 2022. As Seamus Kearney of ARC Regulatory stated at a May 2017 workshop, “The new IVDR marks a sea-change in the regulation of companion diagnostic (CDx) devices in the European Union, not least the requirements for a performance evaluation that includes significant evidence of clinical performance. Combined with the change in classification for CDx assays from a General IVD to a Class C device, as well as review of the dossier by a Notified Body and the European Medicines Agency (EMA) for medicines, [there will be] a significantly increased burden on diagnostic manufacturers.”

Details of the IVDR

This article focuses primarily on the consequences of the new regulation on CDx and its effect on the use of laboratory developed tests (LDTs).

The EU IVDR* was published in the Official Journal of the EU on 5 May 2017, entering member states’ law on 25 May 2017. The legislation, which has a five-year transition period, with full entry coming into force on 26 May 2022, will involve some significant changes to how IVDs are regulated in the EU. These changes include:

  • Revised definition of IVDs
  • Moving to a risk-based classification similar to those used by other regulatory authorities (e.g., FDA and Japan)
  • Defining and regulating companion diagnostics as distinct entities, placing considerably more work onto Notified Bodies (NB): under the old directive around 20 per cent of devices had to be reviewed by NB but this figure will rise to about 80 per cent under the new regulation
  • No ‘grandfathering’: all devices on the market on 26 May 2022 must be compliant with the new regulation regardless of how long they have been on the market prior to that date. Given the cost of additional studies required to support compliance, this might mean that some low-margin/low-volume diagnostic tests could be withdrawn from the EU market as it may be uneconomic to pass them through the revised regulatory approval.

So how does the new regulation affect companion diagnostics and, in particular, the use of laboratory developed tests (LDTs, ‘home brew’ or ‘in-house manufactured assays’), a favoured route for testing in many European labs?

Article 2(7) of the IVDR states:

‘companion diagnostic’ means a device which is essential for the safe and effective use of a corresponding medicinal product to:
(a) identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or
(b) identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product’

This definition does not encompass complementary diagnostics, defined (at least by the FDA) as “…a test that aids in the benefit-risk decision making about the use of the therapeutic product, where the difference in benefit-risk is clinically meaningful”.
Companion diagnostics will be classified as Class C (the second highest risk level) devices, meaning companies wishing to place CDx into the market will require interaction both with NB and the national competent authorities (CAs) for medicines (or the European Medicines Agency) regulating the therapy to which the CDx refers. Regulation of CDx will require a summary of safety and performance and a full Quality Management System (QMS) with technical file review of at least one device per generic group (Annex IX except Chapter II) or EC type-exam (Annex X) with production quality assurance or EC verification (Annex XI). Class C genetic tests will require patient counselling to be put in place, however, this requirement is exempt for CDx.

What this means for pharma

The greater degree of regulation for CDx compared to the current regulatory paradigm in the EU will likely necessitate more careful planning and integration of regulatory applications for the therapy and its CDx, as both will be regulated in tandem. Pharma teams will need to engage with their CDx partners and relevant NB at a very early stage of the development process to ensure correct integration of regulatory approval for the test into the regulatory approvals for their asset.

Representatives from different NBs have commented that the IVDR remains something of a work in progress, with specifics still to be ironed out. There are no plans for implementation acts covering the regulations around LDTs other than those in Annexe I, which therefore leaves some areas of uncertainty how the regulation is to be applied to these types of test.

The rulings around LDTs

The IVDR prefaces the regulation of LDTs with the statement:

“Health institutions should have the possibility of manufacturing, modifying and using devices in-house and thereby addressing, on a non-industrial scale, the specific needs of target patient groups which cannot be met at the appropriate level of performance by an equivalent device available on the market (author emphasis added). In that context, it is appropriate to provide that certain rules of this Regulation, as regards devices manufactured and used only within health institutions, including hospitals as well as institutions, such as laboratories and public health institutes that support the health care system and/or address patient needs, but which do not treat or care for patients directly, should not apply, since the aims of this Regulation would still be met in a proportionate manner. (Para 29 of opening section.)

Specific regulation for LDT is given in Article 5(5):

“With the exception of the relevant general safety and performance requirements set out in Annex I, the requirements of this Regulation shall not apply to devices manufactured and used only within health institutions established in the Union, provided that all of the following conditions are met:
(a) the devices are not transferred to another legal entity;
(b) manufacture and use of the devices occur under appropriate quality management systems;
(c) the laboratory of the health institution is compliant with standard EN ISO 15189 or where applicable national provisions, including national provisions regarding accreditation;
(d) the health institution justifies in its documentation that the target patient group’s specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market (author emphasis added);
(e) the health institution provides information upon request on the use of such devices to its competent authority, which shall include a justification of their manufacturing, modification and use (author emphasis added);
(f) the health institution draws up a declaration which it shall make publicly available, including:
(i) the name and address of the manufacturing health institution,
(ii) the details necessary to identify the devices,
(iii) a declaration that the devices meet the general safety and performance requirements set out in Annex I to this Regulation and, where applicable, information on which requirements are not fully met with a reasoned justification therefore;
(g) as regards class D devices in accordance with the rules set out in Annex VIII, the health institution draws up documentation that makes it possible to have an understanding of the manufacturing facility, the manufacturing process, the design and performance data of the devices, including the intended purpose, and that is sufficiently detailed to enable the competent authority to ascertain that the general safety and performance requirements set out in Annex I to this Regulation are met. Member States may apply this provision also to class A, B or C devices in accordance with the rules set out in Annex VIII;
(h) the health institution takes all necessary measures to ensure that all devices are manufactured in accordance with the documentation referred to in point (g); and
(i) the health institution reviews experience gained from clinical use of the devices and takes all necessary corrective actions.
Member States may require that such health institutions submit to the competent authority any further relevant information about such devices which have been manufactured and used on their territory.
Member States shall retain the right to restrict the manufacture and use of any specific type of such devices and shall be permitted access to inspect the activities of the health institutions.
This paragraph shall not apply to devices that are manufactured on an industrial scale (author emphasis added).”

There is clearly going to be a greater degree of regulation imposed on LDTs than has hitherto been the case including:

  • Drafting justifications for laboratories’ use of LDT instead of commercially-available kits/assays. Simple cost per test will not represent a sufficient justification
  • Monitoring both the performance of the test and the clinical justification for its use
  • Maintaining documentation about the manufacture and use of the test
  • Ascertaining if the national competent authorities require design, manufacturing and performance data (Para g) for a Class C CDx LDT

Questions arising from the new regulations concerning LDTs

The way in which the regulations governing LDTs are worded does, however, raise a number of questions:

1. “This paragraph shall not apply to devices that are manufactured on an industrial scale” and “…thereby addressing, on a non-industrial scale…” begs the question: what is meant by a non-industrial scale?
Will the definition of “industrial scale” in respect of LDT, absent from the previous regulations, be left to national competent authorities or Member States? This would raise the possibility of a test being allowed as an LDT in one country but not another, depending on the size of the country, the number of labs performing testing, the proportion of patients with the condition being tested, etc.

2. “(a) the devices are not transferred to another legal entity;”
The regulation describes the manufacturing/testing location as a hospital or institution. However, health trusts in the UK and similar entities in other countries of the EU may encompass a number of locations where manufacture and use of a test could be in separate institutions/hospitals, yet which are part of the same legal entity. Will implementation of the regulation require use of LDTs at only a single site, that of manufacture, or allow transfer within a legal entity as implied by the wording of the regulation?

3. “…the health institution justifies in its documentation that the target patient group’s specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market…”
This raises a number of potential issues:
(i): What is meant by appropriate level of performance?
In the case of CDx, this may have to be defined in relation to the drug which the physician treating the patient intends to use, should the CDx result indicate it is appropriate to do so. Where the drug is approved for more than one indication, “appropriate level of performance” may also have to be determined by the indication, if the cut-offs in different indications straddle the limit of sensitivity of the test.

(ii): Consider this these two scenarios:
A hospital lab has an LDT for gene mutations A, B, C and D in a particular gene. There is no mutation test commercially available for A, B, C and D, however, there are two commercial tests on the market, one for A and D, and one for B and C, but none for combined genes A, B, C and D. Performance in terms of sensitivity for determining mutations are similar for the LDT and for the commercially-available tests.
Does the combination of the two commercially available tests constitute an ‘equivalent’ device on the market? The strict answer has to be ‘no’, however, there are two commercially available tests which when combined produce an equivalent device, i.e., a test for genes A, B, C and D. Would the fact that two tests available on the market, whose results combined provide the same results as the LDT, be regarded as an ‘equivalent test’?
What if the two tests were made by the same, or separate, companies?
Would the lab be expected to buy and use the two commercially available tests to obtain equivalent results to its own LDT and, given cost constraints on testing in health service labs, to what extent would this happen in practice?

(iii): A hospital lab has a lab- developed immunohistochemical (IHC) test for a particular biomarker which it runs on an automated staining platform made by company A.
Company B produces a kit for IHC of the biomarker designed to run on its own automated staining platform.
If the hospital does not have a company B platform, does this mean that its own LDT has no commercially available equivalent (i.e., a test for the analyte which runs on the platform of company A)?
Would the lab be expected to run the company B kit on their company A platform?
This would, in effect render the company B kit an LDT.
Would the lab be expected to acquire the company B platform so that it can run the commercially available test and again, as with (ii), would this happen in practice given the cost constraints?


While the IVDR represents an important step forward in the regulation of IVDs in the EU, there are still a number of areas relating to the regulation of CDx and especially LDTs where further guidance and clarification are required. This uncertainty should not be left to individual member countries but needs to be implemented consistently across the EU. Updates to the IVDR may be forthcoming during the five-year run up to full implementation, but labs and pharma need to be aware of potential gaps in the regulation and be prepared to work with their NB and CAs to ensure compliance.

*Full title: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU, IVDR


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