Integrating IVDs in Medicinal Product Clinical Trials

The integration of in vitro diagnostic devices (IVDs) into clinical trials is reshaping the future of drug development and personalised medicine. These devices, which analyse biological samples to provide critical health insights, are not just supportive tools; they are strategic enablers of precision therapies. In an era where treatment success depends on accurate patient selection and real-time monitoring, IVDs, particularly companion diagnostics (CDx), have become indispensable.

This article aims to demystify the regulatory pathways, challenges, and strategic considerations involved in incorporating IVDs into medicinal product trials. It explores the evolving frameworks under Regulation (EU) 2017/746 and the UK Medical Devices Regulations 2002, as amended, highlighting performance evaluation requirements and examining practical approaches for sponsors navigating this complex landscape.

Why is this relevant? Regulatory expectations for IVDs have intensified, and missteps in classification or validation can lead to costly delays. Understanding these requirements early ensures compliance, accelerates trial timelines, and enhances the likelihood of successful approvals.

By reading this article, you will:

• Understand the critical role of IVDs and CDx in precision medicine.
• Learn key regulatory obligations under EU and UK frameworks.
• Discover strategic planning tips to streamline trial design and avoid common pitfalls.
• Gain insights into future trends, including AI-driven diagnostics and global harmonisation.

 

Whether you are a sponsor, CRO, or manufacturer, this guide provides actionable strategies to integrate diagnostics effectively, ensuring your trials are scientifically robust and regulatory-ready.

 

Specialised IVDs in Clinical Trials

In vitro diagnostic (IVD) medical devices are essential tools in modern healthcare, enabling the detection, monitoring, and prediction of diseases through the analysis of biological samples.

An IVD in the European Union is defined under Regulation (EU) 2017/746 as any device, such as reagents, instruments, software, or kits, intended by the manufacturer for the in vitro examination of human specimens (e.g., blood, tissue) to provide information about health status, disease, or treatment response. These devices play a critical role in diagnostics, screening, and monitoring, and are regulated to ensure safety, performance, and reliability.

In clinical trials, IVDs play a pivotal role in patient stratification, treatment monitoring, and outcome assessment. The importance of IVDs is magnified in the era of precision medicine, where personalised therapies rely on accurate diagnostic tools to identify suitable patient populations. Companion diagnostics (CDx), a subset of IVDs, are particularly critical as they guide the safe and effective use of specific therapeutic products.

CDx are specialised in vitro diagnostic tests that help determine whether a patient is likely to benefit from a specific therapeutic product. They are essential tools in personalised medicine, enabling tailored treatment strategies based on a patient’s unique genetic and biological profile.

CDx tests serve several key functions:

• Identify suitable patients for targeted therapies.
• Predict adverse reactions, enhancing treatment safety.
• Monitor treatment response, allowing for timely adjustments.
• Improve drug efficacy by ensuring therapies are used in the right patient populations.

 

CDx are co-developed with therapeutic drugs and are essential for identifying patients who are most likely to benefit from a particular treatment or who may be at increased risk of adverse reactions. Developed initially alongside cancer therapies like trastuzumab (Herceptin), CDx have expanded across various diseases, including rare and metabolic conditions. Their use streamlines clinical trials, reduces costs, and increases the likelihood of regulatory approval by focusing on patients most likely to respond.

As healthcare shifts toward individualised care, CDx are becoming indispensable in delivering more effective, safer, and cost-efficient treatments.

 

Regulatory Landscape

European Union (EMA and IVDR)

The European Union’s regulatory framework for IVDs is governed by Regulation (EU) 2017/746, known as the In Vitro Diagnostic Regulation (IVDR). IVDs are classified into four risk classes (A, B, C, and D) based on intended use and potential health risks. The IVDR replaced the previous In Vitro Diagnostic Directive 98/79/EC (IVDD) and introduced more stringent requirements for clinical evidence, device classification, and conformity assessment. Under IVDR, performance evaluation for IVDs is a mandatory process designed to confirm that an IVD not only functions as intended but also produces results that are clinically relevant and reliable. Performance evaluation includes three key pillars: scientific validity, analytical performance, and clinical performance. Together, these elements ensure that IVDs deliver accurate and clinically meaningful data for patient care and trial outcomes.

The strengthened requirements under the IVDR also apply to CDx, which are now classified as Class C devices. This classification triggers additional regulatory oversight, including the involvement of Notified Bodies and a scientific consultation with the European Medicines Agency (EMA) to ensure the CDx aligns with the therapeutic context of the associated medicinal product. The EMA has issued guidance to support the integration of CDx in medicinal product development, emphasising the need for robust data, early planning, and alignment with therapeutic indications.

Once an IVD has undergone a conformity assessment appropriate to its risk class, ensuring it meets the general safety and performance requirements, it can be CE marked. CE marking is the official indication that an IVD complies with the safety, performance, and quality requirements under the IVDR. The CE mark is essential for placing IVDs on the EU market, providing assurance to healthcare professionals and patients that the device is both safe and effective for its intended purpose.

 

In-House Manufactured IVDs

The IVDR also introduces specific provisions for in-house manufactured tests used within health institutions, often referred to as Laboratory Developed Tests (LDTs). While these devices are exempt from full conformity assessment, institutions must meet strict conditions: the tests must be developed and used solely within the same health institution, not transferred to another legal entity, and comply with appropriate quality management systems. Additionally, institutions must justify the exemption by documenting why equivalent CE-marked devices cannot meet the intended purpose and ensure compliance with ISO standards such as ISO 15189 (requirements for quality and competence in medical laboratories). These requirements aim to balance innovation in diagnostic testing with patient safety and regulatory oversight.

 

Requirements for IVDs in EU Clinical Trials

IVDs that are used in clinical trials within the EU need to be either CE marked and used as per their intended purpose or an investigational device. Non-CE-marked devices must comply with the IVDR’s performance evaluation provisions. Where a performance study is required, a formal application or, in some cases, a notification to the relevant competent authority and ethics committee approval will need to be obtained before initiating the study. The application must detail the device’s intended purpose, analytical and clinical performance characteristics, and risk management measures. Sponsors are also required to provide a performance evaluation plan, informed consent documentation, and evidence of compliance with Good Clinical Practice (GCP) and ISO 20916 standards for IVD performance studies. These requirements ensure that non-CE marked devices are rigorously assessed for safety, reliability, and clinical relevance before being used to support medicinal product development.

 

Great Britain (MHRA and UK MDR)

In Great Britain, the regulation of IVDs is overseen by the Medicines and Healthcare products Regulatory Agency (MHRA) under the UK Medical Devices Regulations 2002. Following Brexit, Great Britain retained the European Union’s IVDD and incorporated its provisions into UK law via the UK Medical Devices Regulations 2002 (UK MDR). This means that IVDs placed on the GB market must meet requirements largely aligned with the IVDD, including essential safety and performance standards, and conformity assessment routes.

Under transitional arrangements, CE-marked IVDs compliant with IVDD can continue to be marketed in Great Britain until the earlier of certificate expiry or 30 June 2030, easing the shift to the UK’s future regulatory framework.

As part of the regulatory shift, the UK Conformity Assessed (UKCA) marking has replaced the CE marking for devices marketed in Great Britain (England, Scotland, and Wales). Northern Ireland continues to follow EU medical device and IVD regulations, including the IVDR, under the terms of the Northern Ireland Protocol. This means that CE marking remains mandatory for placing IVDs on the Northern Ireland market. During the ongoing transition period in Great Britain, CE-marked devices continue to be accepted, allowing manufacturers time to adjust to the new conformity requirements.

 

Health Institution Exemption

A notable feature of the UK framework is the Health Institution Exemption, which permits the use of in-house manufactured IVDs within the same health institution without undergoing full conformity assessment. This exemption is conditional: the device must be manufactured and used on the premises of the institution or in its immediate vicinity, and must not be transferred to another legal entity. Institutions must also demonstrate compliance with quality standards, such as UKAS accreditation to ISO 15189 and maintain documentation to justify the exemption.

 

Requirements for IVDs in UK Clinical Trials

For clinical trials in the UK involving IVDs that are not CE or UKCA marked, including CDx, sponsors are required to submit detailed documentation to MHRA. This includes either an analytical performance summary report or a tabular summary outlining the intended performance characteristics of the device. If the IVD is exempt under the Health Institution Exemption, additional documentation such as instructions for use (IFU), specimen handling procedures, and instrument validation reports must be submitted via the Integrated Research Application System (IRAS) under the combined review process.

As the UK continues to refine its post-Brexit regulatory landscape, stakeholders are encouraged to stay informed through MHRA guidance updates and consultation documents.

 

Strategic Planning for Clinical Trials Involving IVDs

Effective strategic planning for clinical trials involving IVDs begins with the early identification of biomarker and diagnostic needs. This foundational step ensures that the trial design aligns with the intended diagnostic purpose, whether for patient stratification, treatment monitoring, or therapeutic guidance. The classification of the IVD – as Research Use Only (RUO), Laboratory Developed Test (LDT), or Companion Diagnostic (CDx) – is a critical determinant of the regulatory pathway, influencing both the scope of performance evaluation and the level of regulatory oversight required.

Each classification carries distinct implications:

• RUO devices are not intended for clinical decision-making and must not be used for patient management.
• LDTs, also known as in-house devices, typically developed and validated within a single laboratory or health institution, may be subject to exemptions but still require robust internal quality systems.
• CDx devices, which guide the use of specific medicinal products, face the most stringent requirements, including performance validation and regulatory consultation.

 

To navigate these complexities, cross-functional collaboration is essential. Clinical teams must work closely with regulatory affairs, laboratory scientists, and quality assurance professionals to ensure that the diagnostic strategy is scientifically sound and compliant with applicable regulations. This collaboration helps to mitigate risks, avoid protocol deviations, and ensure that diagnostic components are appropriately integrated into the trial.

Sponsors must also anticipate potential regulatory delays, particularly when dealing with novel biomarkers or CDx devices that require engagement with regulatory bodies such as the MHRA in the UK or EMA in the EU. Early planning for performance evaluations, including analytical and clinical validation studies, is crucial to avoid bottlenecks that could impact trial timelines or data integrity.

In an increasingly complex regulatory landscape, planning and interdisciplinary coordination are key to the successful execution of clinical trials involving IVDs, ensuring both regulatory compliance and scientific rigour.

 

Performance Evaluation

Under the IVDR, performance evaluation is a continuous and structured process that spans the entire lifecycle of an IVD. It encompasses both analytical performance and clinical performance studies, each serving distinct but complementary roles in demonstrating the safety, reliability, and clinical utility of the device.

Analytical performance focuses on the technical capabilities of the IVD, assessing parameters such as sensitivity, specificity, accuracy, precision, reproducibility, and limits of detection. These studies ensure that the device consistently produces reliable results under defined conditions.

Clinical performance, on the other hand, evaluates the device’s ability to correlate test results with a specific clinical condition or physiological state. This includes demonstrating the diagnostic sensitivity and specificity in real-world settings, often through formal clinical studies or, where justified, through published literature and routine diagnostic data.

 

Medical Device Coordination Group (MDCG) Guidance

The Medical Device Coordination Group (MDCG) has issued MDCG 2025-5, a comprehensive guidance document that clarifies the regulatory expectations for performance studies under IVDR. This guidance outlines:

• When performance studies are required, including for CE-marked devices used outside their intended purpose or in post-market performance follow-up (PMPF).
• Special provisions for CDx, which are subject to Article 58(2) due to their role in guiding medicinal product use.
• Requirements for studies using leftover samples, which may qualify for notification rather than a full application, depending on the study design.
• Decision trees and flowcharts to help sponsors determine whether a study requires notification, application, or no submission to competent authorities.
• Responsibilities of sponsors and investigators, including ethical review, safety reporting, and handling of substantial modifications during ongoing studies.

 

Importantly, MDCG 2025-5 emphasises that analytical performance must always be demonstrated through study data, while clinical performance may be supported by a combination of clinical studies, peer-reviewed literature, or routine diagnostic use, provided the justification is robust and scientifically sound.

This evolving framework underscores the importance of early planning, cross-functional collaboration, and regulatory engagement to ensure that performance evaluation activities are aligned with IVDR requirements and support the successful market access of IVDs in the EU.

Under the IVDD, performance evaluation was largely implicit, focusing on analytical performance like sensitivity and specificity, with minimal guidance on clinical evidence or lifecycle management. Manufacturers often relied on internal validation and literature reviews to support claims. The IVDR transformed this approach by introducing more stringent requirements to ensure performance evaluation changes from a one-time check to an ongoing, evidence-driven process, ensuring patient safety and device reliability.

 

Real-World Integration of CDx in Clinical Trials

CDx have become a cornerstone of precision oncology, where biomarkers guide patient selection for targeted therapies. These diagnostics enable sponsors to identify subpopulations most likely to benefit from a treatment, improving trial efficiency and therapeutic outcomes. For example, HER2 testing in breast cancer trials ensures that only patients with HER2-positive tumours receive trastuzumab, while EGFR mutation testing in lung cancer trials directs the use of tyrosine kinase inhibitors. These approaches reduce variability, improve efficacy signals, and enhance patient safety.

Combined trials involving both medicinal products and IVDs present unique regulatory challenges. Sponsors must coordinate submissions across medicinal and device frameworks, ensuring that performance data, including analytical and clinical validation, aligns with therapeutic indications. This often requires early engagement with regulatory authorities such as the EMA or MHRA to streamline review processes and avoid delays.

During the IVDR transition period, legacy IVDs certified under the IVDD may continue to be used , provided they meet established quality and performance standards. However, sponsors should anticipate stricter requirements for post-market surveillance and performance evaluation under IVDR, particularly for high-risk devices like CDx. Proactive planning and robust documentation are essential to maintain compliance and support the integration of diagnostics into innovative trial designs.

 

Common Challenges and Solutions

Clinical trials involving IVDs often face significant operational and regulatory hurdles. Among the most common challenges is the misclassification of IVDs, which can lead to incorrect regulatory pathways and delays in trial initiation. For example, a device intended as a CDx may mistakenly be treated as a RUO product, resulting in non-compliance with performance evaluation requirements under IVDR or MHRA guidance.

Another persistent issue is the lack of harmonisation across jurisdictions. Global trials frequently span regions governed by different regulatory frameworks, such as IVDR in the EU, UKCA requirements in Great Britain, and even differing requirements on a competent authority level. Divergent definitions, timelines, and documentation standards create complexity for sponsors, who must reconcile these differences without compromising trial integrity or timelines.

The complexities of data submission for combined trials, where both a medicinal product and an IVD are evaluated, add another layer of difficulty. Coordinating performance data, clinical evidence, and regulatory submissions across multiple authorities requires meticulous planning and clear communication between stakeholders.

Solutions to these challenges start with early regulatory engagement, enabling sponsors to clarify classification, performance expectations, and submission requirements before trial initiation. Leveraging harmonised standards, such as ISO 15189 for laboratory quality and ISO 20916 for clinical performance studies, helps ensure consistency and acceptance across regions. Finally, clear documentation of intended use and performance characteristics, including analytical validity, clinical validity, and clinical utility, provides regulators with confidence in the device’s role and reliability, reducing the risk of delays or rejection.

By adopting these strategies, sponsors can navigate the complex regulatory landscape, mitigate risks, and accelerate the development of innovative diagnostics that support precision medicine.

 

Future Outlook

The role of IVDs in clinical research is rapidly transforming, driven by breakthroughs in digital diagnostics, artificial intelligence (AI), and machine learning algorithms. These technologies enable faster, more accurate interpretation of complex datasets, such as genomic profiles and multiomics biomarkers, which are increasingly used to guide patient selection and treatment decisions. AI-powered assays can detect subtle patterns in imaging or molecular data, improving diagnostic precision and supporting adaptive trial designs where treatment strategies evolve based on real-time results.

At the same time, regulatory convergence efforts, led by organisations such as the International Medical Device Regulators Forum (IMDRF), are working to harmonise global requirements for IVDs, including software-based diagnostics. Harmonisation reduces duplication, accelerates approvals, and fosters innovation by creating predictable pathways for multinational trials.

For sponsors, these developments mean that staying informed and agile is no longer optional. Emerging technologies bring new regulatory expectations, such as cybersecurity for connected devices, validation of AI algorithms, and transparency in data handling. Sponsors must integrate these considerations early in trial planning, engage proactively with regulators, and adopt international standards like ISO 20916 for clinical performance studies and IEC 62304 for software lifecycle processes. Those who adapt quickly will be best positioned to leverage digital diagnostics and AI-driven tools to deliver personalised, efficient, and globally compliant clinical research.

 

Conclusion

In vitro diagnostic devices (IVDs), particularly companion diagnostics (CDx), are now central to the success of clinical trials and the advancement of personalised medicine. Their integration enables precise patient stratification, enhances therapeutic efficacy, and supports adaptive trial designs. Regulatory frameworks such as the EU IVDR have introduced rigorous performance evaluation requirements, underscoring the need for robust analytical and clinical validation. The evolving landscape, including AI-driven diagnostics and global harmonisation efforts, presents both opportunities and challenges for sponsors.

Key recommendations for sponsors and CROs include:

Start early: Identify biomarker and diagnostic needs during trial design to align with regulatory expectations.

Classify correctly: Ensure accurate categorisation of IVDs (RUO, LDT, CDx) to avoid missteps in regulatory pathways.

Collaborate cross-functionally: Engage clinical, regulatory, laboratory, and quality teams to ensure scientific and operational alignment.

Plan for performance evaluation: Anticipate analytical and clinical validation requirements, especially for CDx, and prepare comprehensive documentation.

Leverage harmonised standards: Adopt ISO and IEC frameworks to streamline multinational submissions and ensure quality assurance.

Above all, proactive regulatory engagement is essential. Early dialogue with authorities such as the EMA and MHRA can clarify expectations, reduce delays, and facilitate smoother integration of diagnostics into clinical trials. Sponsors who embrace strategic planning and regulatory foresight will be best positioned to deliver innovative, compliant, and patient-centric research outcomes. At DLRC, we support this process by providing expert guidance on regulatory strategy, planning, and submissions. Our team helps sponsors anticipate challenges, align with evolving EU and UK requirements, and maintain compliance throughout the product lifecycle. This ensures your diagnostics and medicinal products reach patients efficiently and successfully. To learn more, contact our experts at hello@dlrcgroup.com.