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Integrating Performance Studies of In-Vitro Diagnostics into Clinical Trials: A Complex Challenge

Clinical Performance Studies Under the EU IVDR

On 26 May 2022, the Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) replaced the In-vitro Diagnostics Directive (IVDD). The IVDR introduced a risk-based classification system for in-vitro diagnostic (IVDs) medical devices and more stringent requirements for technical documentation and clinical evidence. 

Clinical performance studies are research studies conducted to evaluate how well an IVD performs in clinical settings. They assess the product’s performance, such as its accuracy, sensitivity, specificity, and reliability. Clinical performance studies aim to generate evidence on the effectiveness and safety of the IVD under investigation. The data collected from these studies are crucial for clinical decision-making and for improving patient outcomes. 

Although the intent of IVDR is to drive harmonization across the European Union, some ethical and operational aspects of the clinical performance studies continue to be assessed at a national level. Moreover, in the absence of a fully functional EUDAMED database, national Competent Authorities still maintain country-level requirements and country-specific assessment procedures, which are roadblocks for the implementation of a harmonized submission and assessment process, as foreseen by the IVDR.

Implications of Distinct Submission Procedures in Combined Trials

Integrating performance studies for IVDs within clinical trials (combined trials) presents unique challenges and opportunities. Combined trials involve the simultaneous evaluation of a medicinal product and an IVD, which in many cases will be a companion diagnostic device. A companion diagnostic is defined in Article 2 of IVDR as:

"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."

Companion diagnostics are considered Class C devices according to Annex VIII of the IVDR. This means they are subject to the same performance evaluation requirements as all other Class C devices, with the additional requirement to validate the device together with the associated drug product. A combined trial allows for streamlined data collection, reducing trial duration and costs while enhancing efficiency. 

Such combined trials need to comply with the requirements of both European Union Clinical Trials Regulation (EU CTR) and IVDR. This implies separate applications via distinct procedures, impacting efficiency of approval and start-up timelines and introducing significant regulatory compliance burden. Preparing and submitting separate applications via two very distinct submission pathways must be navigated by Sponsors and CROs. The two applications are significantly different, but with some overlaps with requirements for study documentation. This overlap requires additional strategic considerations, takes more time/effort, and demands expertise, potentially impacting the initiation and conduct of combined trials.

There is the additional complexity for study documentation that is part of both application types (clinical trial and device) and receives different requests for changes during the independent assessment processes. A substantial modification might be required to align the updates and ensure that the same final document is authorised under both approval pathways. Inconsistencies in the requirements, submission documents, assessment and approval pathways and authorisation lifecycle expectations can create confusion and uncertainty, leading in variations in interpretation and implementation in the EU countries where the regulations apply.

Harmonisation Gap in Implementing EU Regulations

Harmonizing implementation of regulations across EU countries remains a complex task. Variations in interpretation and implementation of regulations create disparities and pose challenges for those following and applying the requirements for combined trials. 

On the whole, the implementation of the EU CTR has harmonised medicinal product clinical trial applications, which are submitted via the Clinical Trial Information System portal (CTIS). However, for IVD performance studies, the national submission procedures continue to apply until the upgrade of EUDAMED electronic system. This means that EU CTR and IVDR applications are not linked. They can be submitted either in parallel, before, or after each other. 

Furthermore, the application for performance studies, assessment procedures and timelines are described in Articles 66 and 74 of the IVDR, which define submissions to the Regulatory Authorities (RA) of the Member States involved. However, ethical review of the studies continues to be conducted according to the varying country-specific Ethics Committee (EC) processes. 

Several EU countries, including Czech Republic, Finland, Germany, Hungary, Italy, Poland, Romania, have implemented a sequential (RA and EC) approach to evaluate clinical performance studies. In this approach, the ethical evaluation precedes the RA review, which can only start once the EC opinion is obtained. Consequently, the anticipated review period is likely to be longer compared to the countries that have adopted a parallel RA and EC review approach. The combination of a sequential IVDR evaluation and a parallel EU CTR evaluation for the medicinal product (where both Part I and Part II are assessed simultaneously) may present considerable complexity in those countries. 

The requirements for documentation to be submitted with the clinical performance study application are outlined in Annex XIII and Annex XIV of the IVDR. A more detailed version can be found in a guideline issued by the Medical Device Coordination Group (MDCG). The MDCG 2022-19 Guideline also offers a template for the submission application form. However, several European Union countries, including Belgium, France, Lithuania, have introduced their own application forms. Meanwhile other countries, including France and Portugal, mandate requirements to submit additional documents to those listed in the MDCG guideline. Therefore, it is essential to verify at the national level whether the requirements of the MDCG guideline accurately align with the country-specific requirements.

The COMBINE Project

In June 2023, the European Commission launched the COMBINE project to collaborate among representatives of RAs and ECs, the European Medicines Agency (EMA) and other relevant stakeholders involved with combined trials. The first phase of the COMBINE project is focused on analysing the complexities surrounding combined studies to pave the way for future solutions. By dissecting the challenges faced by these studies, this initial phase aims to set a clear path for addressing these underlying issues in a strategic manner. The Analysis Phase report has been published in April 2024 and the project has now moved on to the second phase, aimed at developing possible solutions to the identified challenges.

The long-term scope of the COMBINE project is to clarify and align the interface between medicinal product clinical trials, performance studies of in-vitro diagnostics, and clinical investigations of medical devices.

Denmark, the Pioneer of National Coordinated Applications

In collaboration with the Danish EC, the Danish Medicines Agency (DMA) developed a guideline  for a coordinated application process for combined trials in Denmark. The process is available for combined studies when Denmark is participating in a mono-national or multinational clinical trial running via the EU CTR, irrespective of whether Denmark is the Reference Member State (RMS) or Member State Concerned (MSC). This coordinated process enables parallel alignment of documents in both application processes and ensures that Sponsors receive simultaneous decisions on both the clinical trial and the clinical performance study.

Sponsors must submit the IVDR application up to five days prior, but no later than, the EU CTR application in CTIS. Specific requirements apply to both cover letters and the list of submitted documents. Validation and assessment for both applications occur concurrently and in accordance with EU CTR deadlines. Requests for information (RFIs) for validation are received simultaneously from both applications, with the same response deadline. It is imperative to submit both responses simultaneously to ensure the applications can be declared valid on the same day (day 0). If not, the coordinated process cannot be completed. The DMA and the assigned EC then assess both the EU CTR and IVDR applications simultaneously and issue RFIs concurrently. Following the submission of responses, a decision on the IVDR application is expected no later than day 45, followed shortly thereafter by the EU CTR decision.

Conclusion

Integrating performance studies of IVDs within clinical trials is a complex yet essential endeavour in advancing healthcare innovation. By navigating the nuances of regulations, embracing collaborative initiatives, and adopting innovative approaches like coordinated application processes, stakeholders can overcome challenges and unlock the full potential of combined trials. As we continue to navigate this evolving landscape, fostering dialogue, sharing best practices, and promoting in-country and in-region harmonisation will be crucial in driving forward progress and improving patient outcomes.

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