By Deborah Borfitz 

September 13, 2022 | The impact of Europe’s In Vitro Diagnostic Medical Devices Regulation (IVDR) on global trials for precision medicine was shared at the recent Next Generation Dx Summit held in Washington, DC. IVDR is finally coming into force and creating “significant challenges” for pharmaceutical companies sponsoring studies involving biomarker testing on EU patient samples, according to Seamus Kearney, CEO and principal consultant with ARC Regulatory Ltd., headquartered in Northern Ireland. 

Concerns about the ability of the EU Medical Device Directive (MDR) to assure the safety of commercially available devices arose with two high-profile scandals in the 1990s, the first involving breast implants and the second metal-on-metal hip prostheses, Kearney shares. This led to the creation of a new MDR system published after much discussion in May 2017 with a five-year transition period given to the IVD sector that ended May 26, 2022. 

Exceptions to the implementation timing for IVDR include class C (intermediate risk) companion diagnostics (CDx) that have until May 2026 to comply, he notes. IVDR differentiates between risk classes from A (low risk) to D (high risk), based on classification rules used in Japan, Australia, and Canada. 

The regulations cover in-house tests—also referred to as laboratory-developed tests (LDTs)—and include specific requirements for CDx as well as rules regarding traceability of devices and distance selling, says Kearney. 

Precision medicine studies require performance evaluations, but LDTs are exempt when used on a non-industrial scale, he continues. EUDAMED will provide an overview of all medical devices available in the EU via six modules, but currently only three modules—one each for actor registration, unique device identification (UDI) and device registration, and notified bodies and certificates—are functional. 

The remaining modules for clinical investigations and performance studies, vigilance and market surveillance may not be available until 2026. Pharma and diagnostic sponsors will be challenged to untangle the legislation, including what they must do and by when, Kearney says. 

‘Do Not Dither’ 

Given the dearth of information and guidance, theoretical examples are useful, says Kearney. Consider, for instance, a phase 1 global trial involving a partnering biomarker testing lab in the United States and 20 study sites, five of which are in the EU. 

Per Article 58 of the IVDR, performance studies involving CDx are considered high risk and/or clinical performance studies would be required unless they are using only leftover samples. However, no “retrospective active” would be needed if the performance studies started or the investigational medicinal product clinical trial application had been submitted in a member state prior to the date of application. In that case, performance studies could continue to operate under the In Vitro Diagnostic Medical Device Directive (the previous regulatory regime).    

Per Kearney’s example, samples collected and processed at the five EU clinical trial sites are sent to a central lab in the U.S. where the samples are tested with the results determining whether patients are enrolled and randomized into the trial or leave the study but continue to be monitored for possible entry at a future date, Kearney continues. 

By virtue of Article 6 (distance sales), the assay must meet the requirements of IVDR since the trial intends to identify patients before treatment who are likely to benefit from it, and the CDx assay has been developed and used in the U.S. to screen EU patients without the intention of obtaining a CE mark for the test, says Kearney. The applicable requirements include all of Articles 57 to 76 covering performance evaluations and performance studies, plus Annex XIII (performance evaluation, performance studies, and post-market performance follow-up) and Annex XIV (interventional clinical performance studies and certain other performance studies). 

As covered in a publication by MedTech Europe, a trade association for the medical technology industry, performance studies need to be conducted in context of a performance evaluation plan, Kearney says. Start early, he advises, once the clinical development plan has been formulated and the EU sites have been identified.  

“Establish early on your diagnostic vendor’s ability and willingness to comply with EU IVDR,” stresses Kearney, including general safety and performance requirements as covered in Annex 1 of IVDR. The reality is that labs in the U.S. often can’t or don’t want to do what is necessary and this can create huge problems for sponsors trying to get trials started. 

Sponsors will also want to appoint a legal representative to act on their behalf in the EU if they do not want to establish a place of business there. Vendors need to be able to complete all applicable deliverables in Annex XIII, including multiple required reports. 

“Do not dither,” Kearney emphasizes, highlighting the importance of obtaining an Annex XIV application form. Further, don’t “conceal or sugar-coat” requirements from diagnostics vendors or the significance of the effort involved, attempt to go it alone, or overlook sample collection kits and their regulatory status in each of the participating countries. 

In-House Testing 

Kearney’s second example was a phase 1 study utilizing local, in-house testing in the EU. LDTs are exempt from the IVDR, provided the health institution is based in the EU and meets the conditions set out in Article 5(5), he says. These include having an appropriate quality management system, complying with international quality and competence standards for medical laboratories, and justifying that the target patient group's specific needs cannot appropriately be met by an equivalent IVD medical device available on the market. “Commercial labs normally do not meet the definition.” 

Because hospitals have had to focus their efforts on dealing with COVID-19, local labs doing in-house testing have been given until 2024 to comply with IVDR. Important considerations include the bias (variability) in study data introduced by different clinical cutoffs across different assays, Kearney says, as well as how to manage sample availability and concordance for bridging to a central lab LDT. Oversight of in-house exemptions is the responsibility of national competent authorities of each member state. 

Sources of guidance and information on IVDR are available on the websites of the European Commission and MedTech Europe, he notes. MedTech Europe also has some white papers jointly produced with the pharmaceutical industry association EFPIA. 

ARC Regulatory Ltd. has separately developed a platform covering the dos and don’ts under the regulatory schemas of 35 countries. The company has worked on over 50 precision medicine studies as global regulatory and research compliance experts and monitoring CRO, he reports.