Coordinating Medicinal Product and Companion Diagnostic Development

Introduction

In today’s era of precision medicine, companion diagnostics (CDx) are reshaping how therapies are developed and delivered. These specialised tests play a vital role in identifying the right patients for the right treatments—maximising benefit and minimising harm. But how are these diagnostics developed alongside new drugs? This blog explores the integrated journey of companion diagnostics during clinical trials.

What are Companion Diagnostics?

A companion diagnostic is an in vitro medical device (IVD) that provides essential information for the safe and effective use of a specific drug. Most commonly, these diagnostics identify patients who are likely to benefit—or those who may be at risk of serious side effects—from a targeted therapy.

CDx devices are not standalone IVDs. They are co-developed in tandem with the drug they support, forming a linked therapeutic-diagnostic pair from early research through to regulatory approval.

From Exploratory Biomarker to Validated CDx in Europe

In the early stages of drug development, assays are often used exploratorily to investigate potential correlations between biomarker expression and treatment response. At this stage, the assay is typically laboratory-developed, with minimal regulatory constraints, and used on a research-use-only (RUO) basis. The transition point occurs when an assay originally used in an exploratory context begins to inform prospective treatment decisions. This includes:

• Moving from retrospective analysis to prospective trial inclusion/exclusion based on assay results
• Applying the assay during the trial to guide clinical care.
• Using assay results for stratification with impact on treatment selection.

Once these uses are planned or foreseeable, the assay:

• Can no longer be considered "exploratory" or "Research Use Only (RUO)",
• Must be treated as an IVD, and
• Requires development in compliance with In Vitro Diagnostic Regulation (IVDR), including Annex I (general safety and performance requirements)

Performance Evaluation in Pivotal Trials

During Phase III trials, the CDx is evaluated in a clinical performance study designed to demonstrate that it is effective, safe, and reliable in a real-world setting. This performance evaluation is governed by a Clinical Performance Study Plan (CPSP) and conducted in accordance with ISO 20916:2019 – In vitro diagnostic medical devices — Clinical performance studies using specimens from human subjects — Good study practice.

Key elements of the performance evaluation include:

- Clinical sensitivity and specificity – The test’s ability to correctly classify biomarker-positive and -negative patients
- Positive and negative predictive values (PPV/NPV) – Its effectiveness at predicting treatment response or non-response
- Inter-laboratory reproducibility – Ensuring consistent results across sites and instruments
- Concordance with reference or comparator assays, if applicable
- Evaluation of interfering substances and matrix effects that could affect performance

The CPSP defines the study’s objectives, population, specimen types, endpoints, statistical analysis plan, and criteria for success. It is a core part of the technical documentation submitted to regulatory bodies.

Complexity in Engaging Individual EU Member State Authorities

Unlike in the U.S., where both drug and device components of a CDx-drug pair can be reviewed within a centralized FDA framework (e.g. CDRH + CDER), in the European Union, coordination is significantly more complex due to fragmented national responsibilities and distinct regulatory pathways:

1. Different Authorities for Drug and Diagnostic Components
The medicinal product is typically assessed by the EMA (for centralized applications) or national authorities (for decentralized/mutual recognition procedures).

The companion diagnostic falls under the IVDR and must be assessed by a Notified Body and, in the case of CDx, requires consultation with a medicinal product authority—often a Member State competent authority responsible for medicines.

2. Lack of a Unified EU Procedure for Combined Trials
No harmonized procedure currently exists for combined trials (i.e., those that simultaneously serve as a clinical trial for the drug and a performance study for the CDx).

Sponsors must engage each Member State’s competent authorities device/diagnostics teams separately, potentially resulting in divergent interpretations, data requests, and approval timelines. This includes engagement with Ethics committees at a national level.

3. Inconsistent Experience and Capacity Across Member States
Not all Member States have equal experience with combined trials or the IVDR consultation process for CDx.

Some authorities may impose additional documentation, clarification steps, or ethics committee involvement, leading to variability in review expectations.

4. Timing and Resource Constraints
The IVDR imposes strict procedural timelines for performance study applications, but coordination with drug trial approvals is not guaranteed.

Sponsors may need to sequence or parallel-track interactions with:

The EudraCT / CTIS system (for clinical trials and clinical performance studies),

Notified Bodies (for IVD conformity assessments),

Competent authorities (for CDx consultation and performance study approval).

Strategic Implications

To navigate this complexity:

Early engagement with Member State authorities is essential. Initiate scientific advice or pre-submission meetings well in advance of pivotal trials.

Develop a regulatory roadmap that incorporates both the medicinal product and CDx timelines, adjusted for national variations in procedures.

Be prepared for iterative feedback loops, where device questions may delay drug trial approvals—or vice versa.

Involve regulatory consultants with expertise in EU device-drug interface early in development, particularly those with established relationships across key EU competent authorities.

Feel free to contact Clinigen for services we can provide in relation to these strategic implications and to aid your co-development of medicinal products and companion diagnostics.