Companion Diagnostics Under IVDR: The Biotech–Diagnostics Bridge

Companion diagnostics (CDx) represent a pivotal intersection between in vitro diagnostics and biotechnology therapeutics, forming a tightly coupled regulatory and clinical pathway where the safe and effective use of a medicinal product is contingent upon the identification of a specific patient subgroup. Under the EU’s In Vitro Diagnostic Regulation (IVDR) (Regulation (EU) 2017/746), the regulatory scrutiny of these devices has intensified, shifting from a largely self-declared conformity process under the previous directive to a system heavily reliant on rigorous clinical evidence, stringent oversight by Notified Bodies, and active involvement from the European Medicines Agency (EMA) and national competent authorities. For biotech companies and diagnostic developers operating in Europe, navigating the IVDR landscape requires a deep understanding of classification rules, the expectations for performance evaluation, and the mechanisms for coordinating with medicinal product regulators to ensure that the diagnostic and the therapy progress in lockstep.

The Regulatory Architecture of Companion Diagnostics in the EU

Unlike the previous IVD Directive (IVDD), which treated companion diagnostics largely as self-certified products (with some exceptions), the IVDR explicitly recognizes the category of “device intended to be used in combination with a medicinal product” and subjects it to a high level of regulatory oversight. The core principle is that a companion diagnostic is not merely a tool for clinical investigation; it is a device that provides information essential for the safe and effective use of a corresponding medicinal product. Consequently, the regulatory framework is designed to ensure that the performance characteristics of the diagnostic are validated in the context of the therapeutic’s benefit-risk profile.

Under IVDR, a companion diagnostic is generally classified as a Class C device, necessitating the involvement of a Notified Body for conformity assessment. This is a significant departure from the IVDD, where many IVDs were self-certified. The involvement of a Notified Body introduces a layer of external scrutiny that mirrors the centralized marketing authorization process for high-risk medicinal products.

Legal Definitions and Scope

The definition of a companion diagnostic under IVDR is precise. It is a device that is essential for the safe and effective use of a specific medicinal product to:

• Identify patients who are suitable for treatment with the medicinal product;
• Identify patients who are likely to be at increased risk of adverse reactions;
• Monitor response to treatment for the purpose of adjusting treatment.

This definition captures the functional dependency between the device and the drug. If the device is merely informative but not essential for the safe use of the drug, it may not fall under the strict companion diagnostic regime, although it will still be subject to IVDR’s general provisions. The regulatory burden is highest where the diagnostic is the gatekeeper to a therapy with significant risks or where the therapy itself is targeted to a small, genetically defined population.

Intersection with the Medicinal Products Framework

The interplay between the IVDR and the Directive on Medicinal Products for Human Use (or the Clinical Trials Regulation) is central to the lifecycle of a companion diagnostic. The EMA and national competent authorities (NCAs) regulate the medicinal product, while the Notified Bodies, under the supervision of the European Commission and national authorities, regulate the device. Historically, this dual oversight created friction and delays. The IVDR attempts to mitigate this through formalized cooperation mechanisms.

Specifically, the IVDR mandates that the Notified Body must consult the EMA or the relevant NCA when assessing a conformity assessment application for a device intended to be used with a medicinal product authorized via the centralized procedure or a national procedure. This consultation is not merely advisory; it is a formal step in the conformity assessment. The opinion of the medicinal product authority carries significant weight regarding the clinical performance evaluation and the intended purpose of the device.

Key Regulatory Obligation: For a companion diagnostic supporting a centrally authorized medicinal product, the Notified Body must seek a scientific opinion from the EMA regarding the device’s suitability in relation to the medicinal product’s safety, efficacy, and quality.

This mechanism aims to ensure that the diagnostic’s analytical and clinical performance characteristics are aligned with the clinical trial data that supported the drug’s authorization. For example, if a drug is approved for patients with a specific mutation detected by a specific assay, the Notified Body must verify that the assay’s analytical sensitivity (limit of detection) and clinical sensitivity are sufficient to identify that patient population accurately, based on the evidence submitted to the EMA.

Classification and Conformity Assessment Pathways

Classification under IVDR is risk-based and deterministic, following Annex VIII of the Regulation. Most companion diagnostics fall into Class C due to the high individual risk and/or public health risk associated with an incorrect result. An incorrect result could lead to a patient being denied a life-saving therapy or being exposed to a drug with severe side effects without benefit.

The conformity assessment procedure for Class C devices involves the application of a Quality Management System (QMS) and a Technical Documentation review by a Notified Body. For Class C devices, the Notified Body must conduct an on-site audit of the manufacturer’s QMS, and may also sample devices from the production process to verify conformity. This is more rigorous than the procedure for Class B devices, which require QMS review but not necessarily an on-site audit for all manufacturers.

Specific Rules for “Device-Drug” Combinations

While most CDx are standalone IVDs, there are scenarios where the diagnostic reagent or kit is physically combined with the medicinal product (e.g., in a radiopharmaceutical kit). In such cases, the regulatory approach depends on the principal mode of action. If the combination is governed by the medicinal products legislation (as is common for radiopharmaceuticals), the entire product is authorized as a medicinal product. However, if the diagnostic component is distinct and essential, the IVDR still applies to the device aspect, often requiring a joint assessment.

For purely in vitro diagnostic kits (e.g., PCR reagents, immunohistochemistry kits), the IVDR applies directly. The manufacturer must demonstrate compliance with the General Safety and Performance Requirements (GSPRs) listed in Annex I of the IVDR. This includes requirements for labeling, information supplied with the device, and traceability (UDI).

Impact of the IVDR Transition on Existing Devices

Many existing companion diagnostics that were grandfathered under the IVDD now face a “rising” classification under IVDR. A device that was self-certified under IVDD (e.g., a genetic test for a specific polymorphism) might be reclassified as Class C under IVDR if it is intended to guide the use of a high-risk therapy. Manufacturers of these legacy devices must engage a Notified Body and obtain a CE certificate under IVDR before the transition periods expire. The transition provisions (Article 110) provide a staggered timeline based on risk class, but the deadline for Class C devices is a critical bottleneck in the industry.

Timelines: Manufacturers of legacy devices must have applied for a conformity assessment by May 2025 to benefit from the transition provisions, with full compliance required by May 2027 for Class C devices (subject to specific conditions and extensions). The pressure on Notified Body capacity is immense, making early application essential.

Performance Evaluation and Clinical Evidence Expectations

The heart of the IVDR framework is the requirement for “sufficient clinical evidence” (Article 56). This is a shift from the IVDD’s requirement for “scientific validity” to a requirement for robust clinical performance data. For companion diagnostics, this requirement is interpreted through the lens of the therapeutic’s clinical context.

Analytical Performance vs. Clinical Performance

Manufacturers must demonstrate both analytical and clinical performance.

• Analytical Performance: The ability of the device to correctly detect the biomarker (e.g., sensitivity, specificity, precision, limit of detection). This is established through well-controlled laboratory studies.
• Clinical Performance: The ability of the device to provide information that is predictive of the clinical outcome (e.g., positive predictive value, negative predictive value). For a CDx, this means demonstrating that the patients identified by the test actually derive benefit from the therapy (or avoid harm).

Under IVDR, clinical performance cannot be established solely by literature review if the device is intended to be used for a specific therapeutic decision. Clinical performance studies are usually required.

Utilizing Data from Medicinal Product Development

A key practical question for developers is: Can we use the data from the drug’s clinical trials to satisfy the IVDR’s clinical evidence requirements? The answer is generally yes, provided the data is relevant and sufficient. The EMA’s assessment reports and the drug’s clinical trial data often contain the necessary evidence to validate the diagnostic’s ability to predict the therapeutic outcome.

However, the Notified Body will scrutinize this data independently. They will look for:

1. Retrospective Analysis: If the diagnostic was developed retrospectively on stored samples from a clinical trial, the manufacturer must justify the representativeness of the sample and the robustness of the assay validation.
2. Prospective Validation: Ideally, the diagnostic’s performance is validated prospectively within the clinical trial setting. This provides the highest level of evidence.
3. Interchangeability: If the manufacturer intends the device to be interchangeable with the drug’s “companion” device used in the clinical trial, they must demonstrate substantial equivalence or conduct bridging studies.

The IVDR emphasizes the concept of the “state of the art.” This means the clinical evidence must be compared against existing diagnostic standards. If a more accurate test exists, the manufacturer must justify why their device is acceptable (e.g., based on cost, accessibility, or specific clinical nuances).

Post-Market Clinical Follow-up (PMCF)

PMCF is a mandatory requirement for Class C devices. For companion diagnostics, PMCF is often integrated into the post-authorization safety studies (PASS) of the medicinal product. The manufacturer of the IVD must have a plan to continuously update clinical evidence based on real-world data. This might involve monitoring the prevalence of resistance mutations or the emergence of new biomarkers that could affect the test’s predictive value.

Practical Challenges for Biotech and Diagnostic Developers

While the regulatory framework is harmonized at the EU level, the practical implementation presents several challenges that require strategic planning.

Notified Body Capacity and Selection

Notified Bodies designated under IVDR are significantly fewer than those under the IVDD. The technical competence required to assess complex molecular diagnostics (e.g., NGS-based tests) is specialized. Biotech companies often find that securing a Notified Body is the longest lead-time item in their regulatory strategy. It is advisable to engage with potential Notified Bodies early, often before the technical documentation is fully finalized, to agree on the clinical evidence strategy.

Data Sharing and Privacy (GDPR)

Companion diagnostics generate sensitive personal health data. The IVDR requires that manufacturers address data protection in their technical documentation. Furthermore, the collection of clinical evidence for performance studies must comply with the General Data Protection Regulation (GDPR). This is particularly relevant when using retrospective data from different Member States. Manufacturers must ensure that patient consent or a legal basis for processing exists for the specific purpose of the performance study.

Divergent National Implementations

While IVDR is a Regulation (directly applicable in all Member States), its enforcement and the interpretation of “clinical evidence” can vary slightly. For example, the requirements for clinical performance studies involving human subjects (Clinical Performance Studies) are subject to national laws on clinical trials (which are harmonized under the Clinical Trials Regulation, but national nuances remain regarding ethics committee approvals).

Furthermore, the “designation” of Notified Bodies is a national competence. A Notified Body designated by a specific Member State (e.g., Germany’s BfArM or France’s ANSM) operates under the supervision of that authority. This can lead to subtle differences in audit focus. Some Notified Bodies may place heavier emphasis on the QMS aspects (ISO 13485), while others may dive deep into the bioinformatics pipelines of NGS tests.

Co-Development of Drug and Diagnostic

The “co-development” model—where the diagnostic and drug are developed simultaneously—is the gold standard for regulatory alignment. However, it is operationally complex. It requires:

• Joint protocols for clinical trials.
• Aligned timelines for regulatory submissions (MAA for the drug, Technical Documentation submission for the device).
• Shared access to clinical trial data for the diagnostic manufacturer.

In the IVDR era, the pressure is on the diagnostic manufacturer to be an equal partner in the clinical trial. The diagnostic cannot be an afterthought; its analytical validation must be as rigorous as the drug’s safety testing.

Strategic Considerations for Market Access

Obtaining the CE mark under IVDR is only the first step. Market access for companion diagnostics is intrinsically linked to the reimbursement and pricing of the associated therapy.

Reimbursement and Health Technology Assessment (HTA)

European payers and HTA bodies (such as G-BA in Germany or NICE in the UK) require robust evidence of clinical utility. The IVDR’s focus on clinical performance aligns well with HTA requirements, but it is not sufficient. HTA bodies look at cost-effectiveness and the impact on the healthcare system.

A diagnostic that is technically compliant with IVDR may still struggle if it does not clearly demonstrate that it prevents the administration of ineffective (and expensive) therapy to non-responders. The “value proposition” of the companion diagnostic must be proven not just to the Notified Body, but to the healthcare system.

Post-Market Surveillance and Vigilance

The obligations for Post-Market Surveillance (PMS) under IVDR are extensive. Manufacturers must maintain a PMS Plan and generate Periodic Safety Update Reports (PSURs). For Class C devices, the PSUR is submitted to the Notified Body annually.

In the context of a companion diagnostic, a “field safety corrective action” (FSCA) might be triggered if a batch of reagents leads to false negatives, potentially exposing patients to ineffective treatment. The coordination of recalls and safety notices between the drug manufacturer and the diagnostic manufacturer is critical. The EMA’s pharmacovigilance database (EudraVigilance) and the EU’s device vigilance database must be synchronized regarding adverse events related to the diagnostic failure.

Conclusion on Operationalizing IVDR for CDx

The transition to IVDR represents a maturation of the European diagnostics market, bringing it closer to the rigorous standards of the pharmaceutical industry. For developers of companion diagnostics, the path to market is no longer a technical formality but a strategic exercise in evidence generation and regulatory negotiation. Success depends on early engagement with Notified Bodies, a deep understanding of the intersection with EMA regulations, and the ability to generate high-quality clinical data that proves the diagnostic is not just analytically valid, but clinically essential.

The regulatory bridge between biotech therapies and diagnostics is now built on the pillars of the IVDR. Crossing it requires a vehicle equipped with robust quality systems, comprehensive clinical evidence, and a clear understanding of the shared responsibility between the device manufacturer and the medicinal product sponsor.