Companion diagnostics
A companion diagnostic is a test essential for the safe and effective use of a corresponding medicine, used to identify the patients most likely to benefit from it or at increased risk from it. It has its own definition and risk class, its approval involves the medicinal authority as well as the notified body, which see different documents, and its development has to converge with the drug's.
What a companion diagnostic is
In the United States, as of 2013, a companion diagnostic is an in vitro diagnostic device or an imaging tool that provides information essential for the safe and effective use of a corresponding therapeutic product. A BRAF V600 mutation test in melanoma is one: it tests a tumour sample, and if the result is positive a BRAF inhibitor can be prescribed.
In the European Union, a companion diagnostic is officially defined as an in vitro diagnostic medical device essential for the safe and effective use of a corresponding medicinal product, to identify before or during treatment either the patients most likely to benefit from that product or those likely to be at increased risk of serious adverse reactions to it. A test that monitors whether the concentration of the medicinal product is within its intended therapeutic window is not a companion diagnostic, and neither is a test used to determine the dosage.
Practitioners differ on how far the European and American definitions diverge. One IVD consultant holds that the two differ slightly, chiefly in that the American definition can also cover monitoring the response to treatment. Another practitioner sees no big difference and a similar goal: under both, the test provides information essential for the safe and effective use of the corresponding product, and it is used to identify the patient, to see whether the patient is likely to benefit, to identify or monitor an increased risk, and to adjust the treatment.
Companion diagnostics are commonly used in personalised medicine, also known as precision medicine. There they serve to ensure the right therapy for the right group of patients at the right time. In oncology, companion diagnostics can predict responders, but these in vitro tests may not identify all of them. One practitioner observed in 2025 that IVDs, and companion diagnostics especially, were being used a lot in clinical trials.
Risk class and what it demands
In the European Union companion diagnostics fall in risk class C, the second-highest class of the IVDR's risk-based classification. The label must carry the intended purpose, state explicitly that the device is a companion diagnostic, and name the corresponding medicinal product. As class C devices, companion diagnostics undergo conformity assessment by a notified body, which assesses both the manufacturer's quality management system and the technical documentation.
A companion diagnostic has to prove a little more than other IVDs. The manufacturer has to show the clinical evidence, namely scientific validity (that it is the right biomarker), analytical performance, and clinical performance demonstrated adequately with a correct study design, and the device's suitability for determining eligibility for the drug also has to be verified.
The authorities and the documents each sees
European conformity assessment of a companion diagnostic involves at least two authorities, the notified body and the medicinal authority. After the manufacturer applies, the notified body reviews the application and carries out the assessment. For a companion diagnostic it must also consult the medicinal authority, either the European Medicines Agency (EMA) or the national competent authority involved in approving the drug, and it sends that authority the draft instructions for use and the draft summary of safety and performance. If both are satisfied, the notified body can issue the EU certificates of conformity for the quality management system under the IVDR and for the technical documentation. Several parties are therefore in play, the IVD manufacturer, the notified body, the drug manufacturer and the medicinal authority, and each has to take care of how it communicates with the others.
When the notified body must seek the EMA's scientific opinion during its review of a companion diagnostic, the consultation process requires additional time. With notified body availability limited, only one companion diagnostic had been approved under the IVDR as of May 2023.
Terms differ even within the device world: a medical device has a summary of safety and clinical performance and an IVD a summary of safety and performance, and for a companion diagnostic such subtle differences suddenly matter.
The medicinal authority is consulted only on the draft instructions for use and the draft summary of safety and performance. So the quality, structure, readability and transparency of the documents each authority sees are key to success. Among the top findings of some notified bodies are a summary with too little information on clinical performance, products with several intended purposes where it is unclear which is the companion diagnostic claim and which is not, and performance studies that do not consider all the sample types. One of the EMA's top complaints is that the summary is too short and lacks what the agency needs to find, to which a manufacturer replies that it is, after all, a summary. One IVD consultant advises a middle ground, with more information for a companion diagnostic than is standard for an IVD, because the summary is written not only for publication but also for the conformity assessment, in which the EMA has only the instructions for use and the summary.
In the United States as of 2013, companion diagnostics usually called for collaboration between a device maker and a pharmaceutical company, and several centres of the Food and Drug Administration were usually involved.
Co-development with the drug
The challenge in developing a companion diagnostic alongside a drug is to fit each of its steps into the right moment of the drug's development. The first, exploratory phase is the proof of concept, which establishes the scientific validity and identifies the appropriate methodology and laboratory tool. Its steps are biomarker identification and selection, scientific validation, assay development and a prototype, and feasibility studies. The clinical phase covers patient stratification and enrolment, protocol design, logistics and clinical performance, and ends in clinical validation. Approval and conformity assessment follow, and because a companion diagnostic is high-risk they carry procedures beyond those of an ordinary CE application: an expert panel opinion, consultation with the EMA, and the involvement of a reference laboratory as needed, depending on the risk or the product. Approval and commercialisation come last. So the design of both the companion diagnostic and the drug's clinical trial has to be right, and the two procedures have to converge at the right moment, or the project is delayed.
In 2018 medicinal products and companion diagnostics were often developed independently, on different schedules and under different regulatory requirements, and paired only towards the end of development, which left a gap in obtaining evidence and validations. One author then expected that co-developing the product and the diagnostic would require more cooperation between the pharmaceutical and in vitro diagnostic industries, and that synergistic business models would enable simultaneous review and approval of both, so that medical writers would be required to prepare and coordinate regulatory documents for both.
For a writer caught between a drug sponsor and a diagnostic manufacturer, whose development timelines and regulations differ widely, speaking both regulatory languages is perhaps a good place to start.