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Understanding Companion Diagnostics Regulation in the U.S. and EU

Regulatory authorities in the United States (US) and the European Union (EU) are responding to the growing role of Companion Diagnostics (CDx) for innovative therapies. These authorities differ in tactical implementation of regulatory coordination and approval.

In the US, the FDA acts as a central authority and requires contemporaneous submission for a drug and its companion diagnostic device. The EU has several parties involved in approval for drugs and CDx: the National Competent Authorities (NCA) of medicinal products designated by the Member States, the European Medicines Agency (EMA) and designated third-party experts known as Notified Bodies. A nuanced understanding of CDx compliance is a critical aspect of regulatory strategy in the growing field of personalized medicine.


CDx were first introduced a quarter century ago when cancer medicine was transformed by the drug Herceptin. Prior to the approval of this monoclonal antibody therapy, women diagnosed with the HER2 oncogene faced bleak prospects. Now survival rates exceed ninety percent.

Herceptin marked the first time a new drug was designed and tested with a CDx. The HercepTest was an immunohistochemical assay that scored patient HER status in breast tissue samples to establish a benefit for trial selection.

Without the accompanying diagnostic, the clinical trial never would have established safety and efficacy among target patients. The FDA approved both the drug and the diagnostic in 1998. The European Medicines Agency (EMA) followed two years later. This gave birth to a new model of drug-diagnostic co-development at the foundation of modern precision (i.e., personalized) medicine.

Since then, the rise of precision medicine has expanded opportunities for In Vitro Diagnostics (IVD) to determine biomarkers that can be paired with patient-specific therapies. CDx has played a particularly influential role in oncology, where a personalized approach increasingly replaces the so-called “trial-and-error” approach of previous, more generalized, and less effective, forms of chemotherapy and radiation. In Europe, approximately half of all cancer drugs in the past 5 years were personalized therapies based on biomarkers. 

In addition to cancer, CDx-linked therapeutics in other conditions like neuropathy, cardiovascular, and metabolic disorders are also adopting the drug-diagnostic co-development model. In the US, the drug- CDx model accounts for a quarter of all new drugs approved, including non-cancer related treatments such as for rare genetic forms of beta thalassemia, hemophilia and mastocytosis. The overall market value of CDx is forecast to double by the end of this decade, from $8 billion in 2022 to $16 billion in 2029.

Key Characteristics of US Regulatory Environment

FDA defines an IVD companion diagnostic device as an “in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product… The use of an IVD companion diagnostic device with a therapeutic product is stipulated in the instructions for use in the labeling of both the diagnostic device and the corresponding therapeutic product, including the labeling of any generic equivalents of the therapeutic product.” Guidance for Industry and Food and Drug Administration Staff In Vitro Companion Diagnostic Devices (Aug 2014).

In the U.S. drug development, CDx is a test used to identify the following:

  • Patients most likely to benefit from the therapeutic product

  • Patients likely to be at increased risk for serious adverse reactions

  • Monitoring of response to adjust treatment for increased safety and efficacy

In a clinical trial, the Sponsor needs to demonstrate the ability to accurately and reproducibly select patients based on this risk-benefit criteria. This often includes a “cut-off criteria” for patients (responders versus non-responders, at-risk for adverse reaction vs. not-at-risk, etc.).

FDA Guidance Document encourages drug developers with following guidance:

  • Early identification of the need for a drug-diagnostic model in clinical trials.

  • Strongly encourages contemporaneous development of the therapeutic product and the companion diagnostic device.

  • A therapeutic product and its CDx require an Investigational Drug Application (IND) and Investigational Device Exemption (IDE) approvals to conduct investigational studies, respectively. 

  • A therapeutic product and a CDx require a New Drug Application (NDA) and Pre-Market Notification approvals (e.g., PMA or 510(k)) for market authorization in the U.S depending on product risk level classifications.

The vast majority of legacy CDx tests have been approved via the PMA procedure, based on Class III (high risk) product risk classification. The FDA/CDRH recently announced it plans to reclassify many IVDs that are currently class III (high risk) into class II (moderate risk). This would allow manufacturers of certain types of tests to obtain marketing authorization through the less burdensome premarket notification 510(k) pathway to demonstrate substantial equivalence instead of a more stringent PMA process.

Key Characteristics of EU Regulatory Environment

The EU established the regulatory link for drugs and companion diagnostics in 2017 when the IVDR (Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical device) was published.

  • IVDR defines a companion diagnostic (CDx) as a device essential for the safe and effective use of a corresponding medicinal product to identify before and/or during treatment patients who are most likely to benefit from the corresponding medicinal product or patients likely to be at increased risk of serious adverse reactions as result of treatment with the corresponding medicinal product (IVDR Article 2(7)). In Europe, the definition of a CDx differs from that in the US, as it does not include devices for monitoring patient response to adjust treatment for increased safety and efficacy.

  • IVDR establishes four risk classes A, B, C, and D in order of lowest to highest risk class, wherein CDx are by default Class C.

A key contrast with the U.S. approach is the consultation procedure between the local NCA, the European Medicines Agency (EMA) and IVDR-designated Notified Bodies. (Notified Bodies are accredited, independent for-profit, third parties under the IVDR, designated by EU member states, that are contracted by manufacturers to assess the conformity of their Quality Management Systems (QMS) and IVDs (depending on its product risk classification) to be placed on the market in the EU).

Drugs and CDx follow different regulatory pathways. Companion diagnostics are approved by Notified Bodies but only after consultation with the NCA of medicinal products designated by the Member States or the EMA. The interplay between these key regulatory stakeholders has the potential for complexity and can require a sophisticated plan that identifies key milestones and decisions and dependencies to ensure accurate scope, planning, and allowing sufficient time for market authorizations.



In the quarter-century since the first CDx was approved in the U.S. and EU, the drug-diagnostic development model has become a cornerstone of precision medicine for oncology and other diseases. Regulatory authorities from both geographies have recognized this and committed to increasingly detailed regulation and guidance. Differences between the regions remain, however, particularly in the level of centralization required to support drug and diagnostics. In the U.S., drug and device manufacturers can focus on the FDA as the singular authority. In Europe it is essential to analyze and monitor the interplay between National Competent Authorities, the EMA, and IVDR accredited Notified Bodies in the drug and device decision process. Developing an integrated strategy early in the drug and CDx design and development process is essential for navigating complex regulatory frameworks to bring novel, safe, and effective drug-diagnostic products to market.

This article was co-authored by the Landrich Group and Qarad, your partners for regulatory strategy on In Vitro Diagnostics in the US and EU markets.


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CDx Model for US FDA Trials

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