Space for Precision Medicine arrives in the Commission Proposal

What does the European Commission’s proposal to amend the transitional provisions in the IVDR mean for biomarker testing in the EU?

On the 14th of October, 2021, the Commission published a proposed regulation to address the significant challenges faced by the In vitro diagnostics industry and the various stakeholders’ ability to comply with the regulations by the current date of application on 26 May 2022. Citing the combined impacts of the COVID-19 global pandemic and limited capacity of Notified Bodies to conduct the legally required conformity assessments, the proposal seeks to amend the transitional provisions for certain in vitro diagnostic medical devices as well as the application of the in-house exemption for devices manufactured and used within a health institution. But what does the proposed regulation mean for the availability of companion diagnostics (CDx) and biomarker testing for precision medicine in the EU? Here we outline each scenario and its potential impact in turn.

Companion Diagnostic devices CE marked in accordance with directive 98/79/EC

The Commission proposal, when adopted, extends the date of application of many requirements of the new regulation for CDx devices that are already, or will be CE-marked in accordance with the existing IVD directive, by the date of application of the IVDR. CDx devices are currently classified as general IVDs and can be CE-marked in accordance with a conformity assessment procedure in the current Directive that does not require the involvement of a Notified Body. However, given that they will be classified as Class C in vitro diagnostics in accordance with Article 47 and Annex VIII of the new regulation, and therefore requiring the involvement of a Notified Body (as well as the EMA/Competent Authority for medicines) in the conformity assessment, the Commission proposal, by amending Article 110, extends the date by which such CE-marked CDx devices can be placed on the market or put into service to 26 May 2026.

This represents a 4-year extension and is a welcome relief to the precision medicine sector as well as to patients, patient groups and clinicians, by ensuring the continued availability of CE-marked devices that are essential for accurately identifying patients likely to benefit from targeted precision therapies. It is important to note though, that while these devices can continue to be placed on the market or put in to service, manufacturers must ensure that other requirements of the regulation are being followed, namely, requirements relating to post-market surveillance, market surveillance, vigilance and requirements for registration of economic operators and devices.

In-house Developed Tests

A significant proportion of biomarker testing in the EU is currently carried out in clinical laboratories using tests that have been developed and validated in-house.  These in-house tests are exempt from the requirements of the current Directive, instead relying on national quality programmes and requirements for clinical laboratories to assure the reliability of results in clinical laboratories.  While many stakeholders consider it far from ideal that a patient is directed to receive a targeted therapy based on the result of a diagnostic test that, in most cases, will have a different clinical cut-off than the test that was used to select patients in a pivotal clinical trial (and is therefore the population on which a precision therapy’s efficacy is demonstrated), the reality is that in-house testing accounts for almost 75% of biomarker testing in the EU for oncology targeted therapy prescription.

While exempt from many of the requirements of the IVDR, in an effort to address the variability of the quality of clinical testing across the EU, in-house developed tests will be subject to significantly more regulatory requirements than hitherto.  These requirements are outlined in Article 5(5) and are known as the ‘in-house exemption’.  The Commission’s proposal, recognising the lack of preparedness of health institution laboratories to comply by the date of application compounded by the potential interruption in the availability of CE tests in clinical labs, have sought to delay the date by which in-house developed test must be in compliance, extending it by 2 years to 26 May 2024.  In addition, the proposal delays until 26 May 2028 the requirement to provide a justification as to why a target patient group’s specific needs cannot be met, or cannot be met at an appropriate level of performance, by an equivalent device available on the market.  This is clearly a necessary step that has been proposed by the Commission in order to ensure the availability of biomarker diagnosis in clinical testing, given the impact on CE-marked test availability arising from the reduction in Notified Bodies and the significant additional regulatory requirements for clinical laboratories described in Article 5(5) of the regulation.

Devices for Performance Evaluation; Planned and Ongoing Interventional Clinical Studies using unapproved biomarker assays for patient selection or stratification

The Commission’s proposal is silent on the transitional provisions for performance evaluations.  Of particular interest to the precision medicine sector is the impact of IVDR on planned and ongoing interventional clinical studies involving unapproved biomarker assays or devices for performance evaluation.  The provisions described in the IVDR, including the Transitional Provisions in Article 110; the Repeal Provisions at Article 112 and; the Entry into Force and Date of Application provisions at Article 113, provide the precision medicine industry with the information required to determine the impact and to prepare for the changes.  Understanding these provisions, their interplay and how they are impacted by other related provisions is essential so that non-compliance does not interrupt the recruitment of patients on to trial, the sponsors’ clinical development programme and regulatory approval/launch of a targeted therapy.

The obligations relating to performance studies in the current Directive shall remain in force until the later of a). the date of application, 26 May 2022, or b). 6 months after the date of publication of the notice of the availability of EUDAMED in the Official Journal of the European Union (OJEU).  Given the well-publicised delays to EUDAMED, it is highly likely that the applicability of the provisions for performance studies under the current Directive shall remain in force until at least the end of Q4 2022.

The significant impact of the IVDR on performance studies, including the need for ethics and competent authority approvals for certain performance studies and the fact that the requirements of the regulation apply irrespective of where EU patient samples are tested, means that the delays to the full functionality of EUDAMED will provide a welcome opportunity for device and pharma sponsors to take the necessary steps to avoid any negative impacts from the IVDR on clinical trial recruitment.  Preparing all of the necessary documentation now for planned and ongoing clinical trials that use unapproved biomarker tests will ensure that delays in ethics opinion and member state approvals of the performance study are avoided.

In conclusion

The Commission proposal is a welcome development and its adoption and publication in the OJEU will proceed in order to mitigate the hugely negative impact on patients across the EU from a failure to act.  This now provides the time for the precision medicine sector to redouble efforts to work together; Pharma, diagnostic manufacturers, central research laboratory testing providers and the clinical laboratory sector, to prepare for the changes and ensure there is no negative impact on clinical development of precision therapies and biomarker testing in clinical practice.

One of the ways we at ARC Regulatory are preparing to support all of the parties involved is through the launch of our online platform, ARC360, which has several resources available to Dx stakeholders in the precision medicine sector to expedite your compliance with IVDR as well as with local regulations for investigational IVDs in precision medicine trials. Get in touch to arrange a demo of ARC360 or to discuss how our consultants can assist in your preparations for the new EU IVDR and all of the complexity it will bring.