Biomarkers and Companion Diagnostics in Oncology

Biomarkers and Companion Diagnostics in Oncology

The field of oncology has witnessed a paradigm shift with the advent of precision medicine, a tailored approach to cancer treatment based on a genetic or molecular understanding of the disease.  

This shift is evidenced by the growing number of clinical guidelines that incorporate genomic profiling and precision medicine, as reflected in recommendations and guidelines from international learned societies.  

Precision oncology plays a crucial role in delivering optimal patient care, by matching each therapeutic intervention with the patient’s molecular profile. Patients are most likely to respond, thereby maximizing benefits. Additionally, it has the potential to avoid untargeted chemotherapy, improving patient safety and quality of life.

For precision oncology, biomarkers are critical enablers in predicting the response to treatments and their potential toxicities.

However, the efficacy of precision medicine can only be as good as both the understanding of the molecular pathophysiology of the target and the ability of the test to accurately and reliably detect and measure molecular biomarkers.

About one third of marketing authorisations in the field of oncology/haematology, approved in EU between 2010 and 2023, are “biomarker driven” indications where patients are identified using an in vitro diagnostic test. A non-exhaustive list of examples of biomarkers used in oncology includes ALK, MET, HER2, PD-L1, RET, EGFR.

Central to this approach is the use of in vitro diagnostics (IVDs), which plays a crucial role in identifying the molecular and genetic characteristics of tumours (biomarkers), enabling personalized treatment strategies.

Key applications of IVDs in oncology can be summarized as (i) IVDs used to identify biomarkers that indicate the presence of cancer or predict how a patient will respond to a particular treatment. For example, the presence of HER2 protein in breast cancer cells can determine the suitability of HER2-targeted therapies. (ii) Genetic tests, such as next-generation sequencing (NGS), which analyse the DNA of cancer cells to identify mutations that drive tumour growth. (iii) IVDs used to monitor the effectiveness of treatment and detect any signs of recurrence.

IVDs developed alongside specific drugs to identify patients who are most likely to benefit from a particular therapy are Companion Diagnostics (CDx). Companion diagnostics ensure that treatments are tailored to the genetic profile of the patient, maximizing efficacy and minimizing unnecessary side effects.

The landscape of IVDs in the European Union has undergone a significant transformation with the implementation of the In Vitro Diagnostic Regulation (IVDR), which came into full effect in May 2022 Regulation - 2017/746 - EN - Medical Device Regulation - EUR-Lex. This regulation replaces the previous In Vitro Diagnostic Directive (Directive 98/79/EC, IVDD) and introduces more stringent requirements to ensure the safety and performance of IVDs, including companion diagnostics.

One of the key aspects of the IVDR is the obligation of the notified bodies (NBs), responsible to assess and certify companion diagnostics in Europe, to consult the European Medicines Agency (EMA) or the national competent authorities before issuing a CE certification for a companion diagnostic. The goal is to ensure that companion diagnostics meet the necessary standards for safety and performance, particularly in relation to their associated therapeutic product(s).

The consultation procedure provides the NB with the opinion of the CHMP/CAT on the suitability of the CDx for use with the concerned medicinal product(s). More information regarding this consultation procedure is available on the EMA webpage: Medical devices | European Medicines Agency (europa.eu).

Since the implementation of the IVD regulation up to the end of 2024, the EMA has completed a total of 24 consultation procedures associated with 55 indications. Most of the procedures were for in vitro tests used in combination with cancer treatments, however biomarkers to determine patient eligibility for specific treatments are also being used in other therapeutic areas including infectious diseases, immune and neurological conditions. The in vitro tests reviewed by EMA were quite diverse, ranging from the traditional immunohistochemistry test performed in paraffin-embedded tissue to the advanced Next Generation Sequencing (NGS).

The link between the in vitro test used as companion diagnostic and the corresponding medicinal product is essential to ensure that the patient population benefiting from the treatment is accurately identified. It is therefore crucial to provide comprehensive information about biomarkers and the tests used for their identification within the Marketing Authorization Application. More information can be found in frequently-asked-questions-medicinal-products-development-and-assessment-involving-companion-diagnostic-cdx_en.pdf.

According to the current IVDR regulation, all in vitro tests used for selecting patients for therapeutic interventions must obtain CE certification by the end of 2028 (Revision of the In Vitro Diagnostic Devices Regulation). Both in vitro diagnostics certified under the previous directive (Directive 98/79/EC, IVDD) and newly developed in vitro diagnostics must comply with this regulation. Consequently, the European Medicines Agency anticipates a significant increase in applications of companion diagnostic consultation procedures in the upcoming months and years.

Antonella Baron and Ana Trullas are senior scientific specialists in the Oncology and Radiopharmaceuticals Office and are coordinating activities related to Companion Diagnostics at the Human Medicines Division, EMA.