Biomarker guided Companion Diagnostic (CDx) tools in precision medicine
Biomarkers are measurable indicators of biological processes and they offer invaluable insights into health and disease. Found in bodily fluids and tissues, they serve as crucial tools in disease detection and management. In cancer, prognostic biomarkers predict disease progression, guiding treatment decisions. Predictive biomarkers identify patients most likely to benefit from specific therapies, optimizing treatment outcomes and minimizing exposure to ineffective and potentially harmful drugs. These molecular messengers also illuminate underlying disease mechanisms and resistance to treatment, driving the development of more targeted therapies. The FDA plays a critical role in ensuring the scientific validity and clinical utility of biomarker assays, fostering their responsible development and use as powerful diagnostic tools.
A Companion Diagnostic (CDx) test is a type of predictive biomarker test and an in-vitro diagnostic (IVD) assay that plays a crucial role in personalized medicine.
Due to their high-risk nature, most CDx assays are classified as Class III medical devices, requiring rigorous premarket approval (PMA) from the FDA. This stringent regulatory pathway, which demands extensive documentation compared to other IVD submissions like 510(k), underscores the critical role of CDx assays in guiding treatment decisions and ensuring patient safety. By identifying specific biomarkers within a patient, CDx tests determine their suitability for a particular therapy. This information is essential for ensuring the safe and effective use of targeted treatments, as it helps match patients with the most appropriate medications while minimizing the risk of adverse reactions and maximizing therapeutic benefits. A landmark example is HercepTest, the first CDx assay to obtain regulatory approval. It is an immunohistochemical assay approved alongside the drug trastuzumab (monoclonal antibody) for HER2-positive metastatic breast cancer, marking a pivotal moment in personalized medicine.
The number of FDA approved CDx tests is steadily increasing and has reached 63 by the end of 2024 from just 9 CDx assays approved by 2010. Hematological and oncological therapies often rely heavily on CDx assays for their clinical value. Without the accurate CDx assays, the clinical utility of most targeted anti-cancer drugs diminishes significantly potentially leading to suboptimal outcomes for patients.
The CDx tests are developed on various platforms, often one biomarker CDx test for one drug. Immunohistochemistry (IHC), Fluorescence In Situ Hybridization (FISH), Polymerase Chain Reaction (PCR), Next Generation Sequencing (NGS) and Imaging are most common platforms for CDx assay development. The first CDx based on the PCR method was approved for BRAF V600 Mutation, namely the cobas 4800 by by Roche. This is a CDx assay used for detection of the BRAF V600E mutation in patients with melanoma, who might be candidates for treatment with vemurafenib (Zelboraf). Several NGS based CDx tests made their way to the FDA approval in recent years.
Companion Diagnostic (CDx) assays, initially limited to cancer, have expanded their scope to include conditions like Hemophilia, Non-transfusion-dependent Thalassemias and Cystic Fibrosis. The emergence of liquid biopsies, coupled with Next-Generation Sequencing (NGS) technologies, has significantly advanced CDx testing. Liquid biopsy is a minimally invasive test that analyzes circulating tumor DNA (ctDNA) in blood samples, offering several advantages over traditional tissue biopsies, including easier repeatability and feasibility in cases where tissue biopsies are challenging. The Guardant360 CDx, from Guardant Health is the first liquid biopsy CDx test approved that leverages NGS technology to provide information on multiple solid tumor biomarkers and to help identify EGFR mutations in patients who will benefit from treatment with TAGRISSO (osimertinib), an FDA-approved therapy for a form of metastatic Non Small Cell Lung Cancer (NSCLC). Unlike older technologies that often required multiple tests to analyze individual genes, Next-Generation Sequencing (NGS) allows for comprehensive tumor profiling with a single test. This enables clinicians to better assess tumor composition and identify clinically significant mutations. The Guardant360 CDx assay utilizes NGS to simultaneously detect mutations in 55 tumor genes, providing a more efficient and informative approach to tumor characterization. Recently, the approval of multigene panel assays from liquid biopsies as companion diagnostics has ushered in a new era of precision medicine, enabling their widespread use in routine clinical settings.
There are certain complexities of clinical trials for therapies that require companion diagnostic (CDx) devices. Since the final CDx is often unavailable during initial trials, "clinical trial assays" (CTAs) are used for patient selection. This necessitates "clinical bridging studies" to connect the trial results obtained using the CTA to the eventual performance of the final CDx. But there are several challenges associated with this bridging process, including data gaps, variability in local tests, and difficulties in evaluating CDx for biomarkers with low prevalence. Scientists are exploring alternative statistical approaches to effectively address these challenges and ensure reliable assessment of the therapy's effectiveness in conjunction with the final CDx.
The pursuit of precision medicine hinges on the power of predictive biomarkers, guiding us towards truly personalized therapies.
As our understanding of molecular mechanisms deepens, these biomarkers have become indispensable, particularly in fields like hematology and oncology where a growing number of drugs are now accompanied by companion diagnostic (CDx) assays. This marks a significant step forward. The emergence of innovative technologies, including multiplex testing, AI-powered algorithms, and functional drug screening, promises to revolutionize precision medicine. However, realizing the full potential of these advancements necessitates a collaborative effort involving researchers, clinicians, and patients to ensure a truly integrated and personalized approach to healthcare.