In the rapidly evolving landscape of healthcare, precision medicine has emerged as a groundbreaking approach to tailor medical treatment to the individual characteristics of each patient. At the forefront of this revolution are companion diagnostics (CDx), an integral component of medical devices that holds the key to unlocking personalized and targeted therapies. Let’s explore the significance of companion diagnostics products in the realm of medical devices and their impact on patient care.
First, what are Companion Diagnostics, exactly?
The term “companion diagnostic” appears, for the first time in literature, in an article published in Nature Biotechnology in 2006.
From a regulatory perspective, companion diagnostics belong to the medical devices category, and are defined as in vitro diagnostic medical devices, falling under the Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) and repealing Directive 98/79/EC and Commission Decision 2010/227/EU.
The definition of Companion Diagnostic, according to the aforementioned regulation, is “a device which is 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
- identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product”.
To facilitate the classification of in vitro diagnostic medical devices (IVDs), the MDCG 2020-16 rev.2 was published.
So: companion diagnostics refer to tests or assays that are designed to identify specific biomarkers or genetic mutations associated with a particular disease. They often measure the therapeutic target itself or closely related partner molecules, giving rise to the so-called predictive biomarkers. Additionally, the response biomarkers measure the effect of the treatment on the disease process, and such components measuring early drug action on the target are called pharmacodynamic (PD) markers.
These diagnostics play a pivotal role in guiding healthcare practitioners, providing information about a patient’s unique molecular profile. When integrated with medical devices, companion diagnostics enable a more precise and individualized approach to diagnosis, treatment, and monitoring.
For instance, a molecular imaging device equipped with companion diagnostics capabilities can not only visualize internal structures but also analyze specific biomarkers, enabling a more accurate diagnosis and/or treatment. Such devices could also be used for defining patients’ eligibility for specific treatment with a medicinal product, via the quantitative or qualitative determination of specific markers identifying subjects at a higher risk of developing an adverse reactions, or identifying patients in the population for whom the therapeutic product has been adequately studied, and found safe and effective.
But not all biomarkers-identifying assays fall in the companion diagnostics category! In particular, whether an IVD qualifies as a Companion Diagnostic hinge on whether detecting the biomarker status is vital for making therapy decisions to ensure the safe and effective use of the medicinal product. Merely meeting the analytical standards to detect a specific biomarker isn’t adequate to qualify as a CDx. For example, devices employed to monitor treatments with medicinal products, ensuring that the concentration of relevant substances in the human body falls within the therapeutic range, are not classified as companion diagnostics.
According to MDCG 2020-16 rev.2 “ For a device to be defined as a CDx, there should be a link to a medicinal product with an International Non-proprietary Name (INN)“.
Usually, companion diagnostic assays are created concurrently with a drug, employing the drug-diagnostic co-development model. The effectiveness of this model relies on the robustness of the biomarker hypothesis formulated during the early research and preclinical stages of drug development.
The path for their regulatory approval in the EU is rather intricate.
Companion diagnostics are, according to the Regulation, classified as Class C – High patient risk and/or moderate public health risk.
As for obtaining market approval for companion diagnostics, the guidelines specify that the notified body must engage with a competent authority designated by the Member States in accordance with Directive 2001/83/EC of the European Parliament and of the Council or the European Medicines Agency (EMA), with the aim of obtaining a scientific opinion, regarding the suitability of the device in relation to the medicinal product concerned. In particular, where the medicinal product falls exclusively within the scope of the Annex of Regulation (EC) No 726/2004, the notified body shall consult the EMA. The regulatory authority for medicinal products, upon consultation, is expected to provide its opinion within 60 days after receiving all required documentation. If justified, this initial 60-day period may be extended for an additional 60 days.
Moreover, the notified body responsible for the conformity assessment is required to enlist one of the EU reference laboratories to verify the manufacturer’s claimed performance through laboratory testing. This verification includes assessing the device’s compliance with the applicable Common Specifications (CS) or other solutions chosen by the manufacturer to ensure a level of safety and performance that is, at minimum, equivalent. Laboratory tests performed by an EU reference laboratory shall in particular focus on analytical and diagnostic sensitivity using the best available reference materials.
Additionally, for all in vitro medical devices, including the companion, performance studies must be set in place.
In the United States of America:
Companion diagnostics are classified as In Vitro Diagnostic (IVD) class III – medical devices that usually support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. To ensure a high standard of both analytical and clinical performance, this category of Medical Devices necessitates the submission of a pre-market approval (PMA) application, which demands the highest level of comprehensive documentation compared to all IVD devices.
To date, the majority of approved companion diagnostics are applied in the oncology field, but new areas are being studied, for example rheumatology.
While the potential of companion diagnostics in medical devices is vast, several challenges exist, including regulatory hurdles, standardization issues, and the need for continued advancements in technology. Moreover, harnessing the potential of artificial intelligence and machine learning for enhanced, swift analysis seems to be a promising step for the future.
Article Issued by Chiara Gazerro
MDCG 2020-16 rev.2 “Guidance on Classification Rules for in vitro Diagnostic Medical Devices under Regulation (EU) 2017/746”, available online: https://health.ec.europa.eu/system/files/2023-02/md_mdcg_2020_guidance_classification_ivd-md_en.pdf
Jørgensen JT, Hersom M. Companion diagnostics-a tool to improve pharmacotherapy. Ann Transl Med. 2016 Dec;4(24):482. doi: 10.21037/atm.2016.12.26. PMID: 28149844; PMCID: PMC5233535.
Jan Trøst Jørgensen (2015) Companion diagnostics: the key to personalized medicine, Expert Review of Molecular Diagnostics, 15:2, 153-156, DOI: 10.1586/14737159.2015.1002470
Mankoff, D. A., Edmonds, C. E., Farwell, M. D., & Pryma, D. A. (2016, January). Development of companion diagnostics. In Seminars in nuclear medicine (Vol. 46, No. 1, pp. 47-56). WB Saunders.
Papadopoulos N, Kinzler KW, Vogelstein B. The role of companion diagnostics in the development and use of mutation-targeted cancer therapies. Nat Biotechnol 2006;24:985-95. 10.1038/nbt1234
Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU
US FDA. Guidance for Industry and FDA Staff. In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions. June 25, 2010. Available online: http://www.fda.gov/downloads/MedicalDevices/…/ucm071230.pdf.