The impact of IVDR, ISO 15189:2022 changes, and the publication of MDCG 2023-1
The impact of IVDR on in-house devices/LDTs
On May 26, 2022 the new Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) has become fully applicable with major consequences not only for manufacturers of IVDs but also for all diagnostic laboratories, particularly those that manufacture in-house IVDs (often called laboratory developed tests or LDTs).
Although an exemption exists and not all requirements of the IVDR are applicable to LTD IVDs, that exemption is only applicable if several conditions are met as we will discuss later in this blog.
With the implementation of the IVDR, EU laboratories, particularly those that manufacture in-house IVDs, are required to comply with EU legislation for the first time, and the workload to meet those requirements is significant.
It is also important to note that the discussion of in-house IVDs is limited to European health institutions. LDTs manufactured outside the EU, for example, by CLIA-certified US laboratories or other non-EU commercial laboratories, are not eligible for the IVDR LTD/in-house exemption neither they can fulfil the conditions set out in article 5(5) of the IVDR. If these companies provide testing on EU patients through institutions outside of the EU, their IVD tests should be in full compliance with the IVDR by now (including conformity assessment with a Notified Body) which sees scrutiny rise to a completely different level than what they are used to.
The only exception is if there was a signed declaration of conformity for a specific test under the IVD directive (IVDD) prior to the 26th of May 2022, which could have granted that test additional transition time based on the IVDR progressive roll-out that is currently in place. This is unusual because non-EU LDTs were not covered by the previous IVDD, and most companies providing these tests in Europe should now be fully compliant with the IVDR.
Article 6 of the IVDR (distance sales) regulates such commercial activities and states that commercial laboratories operating outside of the EU but providing testing to EU citizens must fully comply with the IVDR.
In this blog we will examine key topics such as:
- What conditions must be met in order to continue manufacturing in-house/LDT IVDs in the EU?
- Changes in the new ISO 15189:2022 standard
- MDCG 2023-1 Guidance on the Health Institution Exemption under Article 5(5) of the IVDR, which was recently published.
- What steps should in-house IVD manufacturers take right now?
- How can MDx assist?
Conditions for In-house IVDs and their deadlines
Under the IVDR, IVDs can be manufactured and used within EU health institutions (in-house devices) on a non-industrial scale to address specific target patient group needs, or when there isn’t an equivalent CE-marked IVD on the market.
It is important to note that each EU member state has the right to restrict the use of such devices and therefore we are likely to see differences being applied on a EU level when it comes to restrictions on in-house devices.
However, the following main conditions must still be met for the exemption to apply:
Condition #1 – No transfer of devices [IVDR article 5(5)a]
IVDs such as reagents and control materials may not be distributed to other legal entities. Material distribution for external quality assessment is an exception (see IVDR Art. 1(3)). Documents such as protocols/standard operating procedures (SOPs) may also be distributed because they are not devices. Furthermore, there are no restrictions on testing samples obtained from external sources. As a result, reference hospitals can continue to analyse samples from hospitals that are unable to perform the test in question, as long as it is not done on an industrial scale.
Timeline: in-house IVDs cannot be transferred to other legal entities from 26 May 2022
Condition #2 – Compliance with EN ISO 15189 [article 5(5)b, c]
Diagnostic laboratories that use in-house IVDs must comply with the EN ISO 15189 standard (recently updated to the 2022 version), which specifies quality and competence requirements in medical laboratories. Accreditation is not strictly necessary unless your member state requires it, but it is good to be aware that external audits are a solid foundation for improving a QMS. A QMS established in accordance with ISO 15189 has generally been acceptable amongst the medical laboratory community, however MDCG 2023-1 confirms that compliance to EN ISO 15189 alone is not sufficient for the manufacture of in-house IVDs. The QMS should extend to other areas that are necessary for IVDR compliance, including for example risk management and manufacturing, by making use of appropriate standards particularly if they are harmonised to the IVDR. MDCG 2023-1 suggests that elements of ISO 13485 (medical devices) and ISO 14791 (risk management) should be incorporated in the QMS. In-house test manufacturers will need to determine the best way to comply with ISO 15189 and the IVDR requirements in Annex I concurrently.
Timeline: compliance with ISO 15189 is required by 26 May 2024
What is ISO 15189:2022?
ISO 15189:2022 specifies quality and competence requirements for medical laboratories. ISO 15189 is applicable not only to medical laboratories developing management systems and assessing their competence, but also to users, regulatory authorities, and accreditation bodies confirming or recognizing the competence of medical laboratories.
ISO 15189:2022 vs 2012: main changes!
Because of the alignment with ISO/IEC 17025:2017-General Requirements For The Competence Of Testing And Calibration Laboratories, the management requirements are now at the end of the document.
– Added requirements for point-of-care testing (POCT) (based on ISO 22870:2016) which is a new addition to the standard’s scope.
– A stronger emphasis on risk management: requires laboratory managers to establish, implement and maintain risk management processes and evaluate their effectiveness; and extends risk measures by requiring safeguards that can prevent unintended adjustments of laboratory equipment.
– New terms & definitions: e.g. In vitro diagnostic medical device (IVD), external quality assessment, trueness/measurement trueness and others.
Condition #3 – Justification of use and unmet needs [Article 5(5) d]
The use of CE-IVDs is the default option under the IVDR. Only when no equivalent CE-IVD is available, or when an equivalent CE-IVD cannot meet the specific needs of a target patient group at the appropriate level of performance, is the use of in-house IVDs permitted. This implies that in-house IVDs can be used when they perform better, i.e. when their use benefits patient safety and health. A written statement justifying the manufacture, modification, and use of in-house IVDs should be available for review by the national competent authority, which oversees the enforcement the IVDR and judges the justification’s validity.
One of the most pressing issues is what constitutes an appropriate justification for unmet need. MDCG 2023-1 provides some further clarity that the justification can be based on technical, biological or clinical aspects of the device “e.g. different intended purpose, different clinical conditions, different patient group, different conditions of use, different principles of operation, different approved specimen materials, different critical performance characteristics or different critical technical specifications”. To establish that an equivalent CE marked device does not exist, MDCG 2023-1 recommends that medical laboratories implement a process to examine the market, for example by consulting EUDAMED, the European database on medical devices or other processes. Furthermore, the justification should be reviewed on a regular basis.
Timeline: 26 May 2028 for the justification to be fully available in the health institution documentation. Please note that the competent authority may submit requests for information already from 26 May 2024.
Condition #4 – Public declaration and GSPR compliance [article 5(5)f]
One of the other conditions to continue manufacturing in-house devices is that the health institution prepares a public declaration with the name and address of the manufacturing health institution, the details of the in-house device and confirmation that the device meets the GSPRs set out in Annex I of the IVDR. Where a GSPR is not met in full an appropriate justification is required. This is best addressed by means of a GSPR checklist that should be prepared for the in-house device.
Annex A of MDCG 2023-1 provides a template for this public declaration.
Timeline: public declarations will need to be available by 26 May 2024
Condition #5 – Additional requirements for class D devices [article 5(5) g,h]
The requirements for class D tests are more stringent than those for classes A-C tests. More information on the manufacturing, design, and performance of in-house IVDs is needed. This means that the GSPR for class D tests should be met and documented in greater detail, largely aligned with that produced for CE-IVDs, i.e. in accordance with Annex II’s technical documentation requirements. For example, there should be documentation that demonstrates how the analytical and clinical performance data support the intended purpose of the in-house device.
Timeline: 26 May 2024
Condition #6 – Clinical experience gained [article 5(5) i]
The experience gained from clinical use of the device should be used by the health institution to review the device performance and to take all necessary corrective actions. The strategy for the evaluation of the use of the in-house IVD should be aligned with post-market surveillance requirements and a documented procedure should be in place.
Timeline: processes to review clinical experience gained should be implemented by 26 May 2024
5 actions in-house test developers must take right now.
- Review the IVDR and establish the appropriate regulatory framework for your unique circumstances:
Health institutions based in Europe can make use of article 5(5) in the IVDR to continue manufacturing in-house IVDs under certain conditions.Laboratories that provide testing on European patients but are based outside of the EU (article 6 distance sales), are not granted an in-house exemption and therefore must meet the IVDR in full if they wish to continue to provide testing on EU specimens.
- Review assay portfolio and identify which are in-house IVDs vs CE-IVDs
For health institutions based in the EU: review the possible classification of your in-house IVDs against Annex VIII (Classification rules) of the IVDR. In-house tests that fall in class D will have stricter requirements to fulfil.
- Ensure all conditions have been met for your laboratory to continue manufacturing in-house IVDs
As of May 2022, devices can no longer be transferred to other legal entities. This is likely to be interpreted differently from member state of member state, depending on how healthcare systems are organised in a particular country. You may seek to clarify your circumstances with your national competent authority.Familiarise with the deadlines for each in-house test condition that applies. For example some requirements have applied in May 2022 (e.g. prohibition to transfer devices to another legal entity), whereas others will become applicable from May 2024 (e.g. ISO 15189 implementation) or May 2028 (e.g. written justification for unmet needs of specific target patient groups).Where relevant, ensure that you have documented evidence to support your obligations under article 5(5).
- Implement a suitable quality management system
ISO 15189:2022 has recently been published and has introduced several changes when compared to ISO 15189:2012. However, regulators continue to believe that this standard is insufficient to address the manufacture of in-house IVDs. As a minimum, your quality management system will need to be supplemented with additional controls from other key medical device standards such as ISO 14971 and ISO 13485.
- Conduct a review of your in-house IVD against the general safety and performance requirements (GSPR) in Annex I of the IVDR
The health institution is legally responsible for the public declaration on the in-house IVD and therefore should complete a full review of all relevant GSPRs and ensure that a justification is readily available for any GSPRs that are not met in full.
How can MDx help?
MDx CRO is a leading quality, regulatory and contract research consulting company dedicated to the medical device and diagnostic sectors.
With the introduction of the IVDR, the requirements for in-house devices and laboratory developed tests (LDTs) have grown significantly. Whether you are a health institution in the EU or a commercial laboratory outside of the EU, our MedTech team can assist you in developing a compliance strategy and will be with you every step of the way.
Our IVDR LDT services have been tailored for the needs of in-house test developers and include:
- Regulatory strategy: includes classification review, intended purpose review, technical documentation needs assessment, and a strategic assessment of regulatory needs with a focus on reducing the compliance burden.
- Creation of QMS procedures to meet the requirements of the in-house test environment whilst meeting EU IVDR requirements.
- Assessment of all conditions in article 5(5)
- Gap assessment of your QMS system
- Medical writing
- Creation of technical documentation to support Class D in-house IVDs
- Creation and completion of GSPR checklists
- Support with notified body applications
- Support with competent authority requests
- ISO 14971:2019 gap analysis and implementation
- ISO 13485:2016 gap analysis and implementation
- ISO 15189:2022 gap analysis and implementation
Please reach out today for a consultation with our team of IVD experts.