Companion diagnostics (CDx) provides information essential for the safe and effective use of a corresponding intervention. Clinical practice is shifting to the era of precision medicine, and CDx is increasingly used to identify eligible patients for targeted treatments. The utilization of CDx in drug development is also growing as it plays a vital role in advancing clinical research through precision medicine, targeted therapy, reduction of adverse effects, acceleration of drug approval, and enhanced efficiency.

What are Companion Diagnostics (CDx)

The US Food and Drug Administration (FDA) defines companion diagnostics (CDx) as “a medical device, often an in vitro diagnostic (IVD), which provides information that is essential for the safe and effective use of a corresponding drug or biological product”. IVDs refer to lab tests on samples of bodily fluids, e.g., blood, urine, and saliva, to diagnose, monitor, and manage diseases and conditions.

Due to the heterogeneity of diseases, patients with similar diagnoses may have varied responses to the same intervention, both in terms of safety and efficacy. In cancer, for example, tumor heterogeneity leads to individual variations in tumor microenvironments, resulting in poor prognoses and therapeutic response. Progress in molecular diagnostics and understanding disease mechanisms led to the development of CDx. CDx is typically developed in parallel with the intervention using the drug-diagnostic co-development model.

According to the FDA, companion diagnostics can:

• Identify patients most likely to benefit from a particular intervention
• Identify patients likely to be at increased risk for serious side effects
• Monitor treatment response for a specific intervention to adjust treatment and improve safety or effectiveness.

The use of IVD companion diagnostics is stipulated in the:

• Instructions for the use of the diagnostic device
• Labeling of the therapeutic product and any generic and biosimilar equivalents of the medicinal product.

Companion Diagnostics and Therapeutics Working Together

Increasingly, medicines approved by regulatory authorities recommend or require CDx to identify patient populations eligible for the treatment. In clinical practice, the information and recommendations for the use of a therapeutic for which a CDx is required are essential to enable correct patient identification.

Personalized medicine

With an improved understanding of the molecular mechanisms in the development and evolution of cancer, clinical researchers and clinicians realize that the past treatment approach of one-size-fits-all is not sufficient, and that gave way to precision medicines. CDx works together with precision cancer therapeutics at multiple points of a patient’s diagnostic and treatment journey to target specific disease characteristics, improve patient outcomes, and reduce economic burden.

The management of non-small cell lung cancer (NSCLC) has benefited from CDx by diagnosing genetic modifications, and enabling personalized medicine for patients. Kang et al. (2022) conducted a systematic review to assess the clinical applicability of a CDx test (immunohistochemistry). They found it effective to test for genetic alterations such as EGFR or ALK mutations to determine whether to administer the corresponding NSCLC treatment.

Adaptive therapy

Citing a lack of CDx in personalized cancer treatment, Braig (2022) draws a parallel with adaptive radiation therapy (RT), which relies on imaging techniques to monitor a patient’s tumor and adapt the dose and alignment of RT to match the tumor. He believes that extracellular vesicle (EV) based liquid biopsies will allow medical oncologists to monitor a patient’s tumor over time and concurrently adapt therapies to increase precision.

Imaging-based CDx

Referencing that most FDA-approved CDx tests detect biomarkers in vitro and ex vivo, Liao et al. (2023) highlight the difficulty in dynamically reporting variations of targets in vivo. According to the authors, imaging-based CDx enables patient stratification for targeted treatment and identifying patient populations benefiting from alternative therapies.

The Role of CDx in Advancing Clinical Research

CDx biomarkers can predict the efficacy or toxicity of an intervention and, as such, play an important role in clinical research and the development of novel therapeutics. Researchers deploy large-scale genomic and proteomic analyses to identify biomarkers and apply machine learning (ML) techniques to employ disease-relevant features from large data sets and to improve predictive models.

Data-driven

Digital technologies, artificial intelligence (AI), and advancements in precision medicine have transformed clinical research and the traditional drug discovery and development approach. Providing an industry perspective, Hartl et al. (2021) underlined the need for both translation and precision, with key components being multi-omics profiling, digital biomarkers, model-based data integration, AI, biomarker-guided trial designs, and patient-centric CDx.

Clinical trials using CDx devices (tests) and therapeutic products can yield the evidence needed to determine the safety and effectiveness of both CDx and the therapeutic product. However, the final market-ready CDx would be unavailable at the time of clinical trial enrollment. In its place, clinical trial assays (CTAs) can be used for patient enrollment, and clinical bridging studies facilitate the bridging of the clinical efficacy of therapeutic products from CTA to CDx.

Precision medicine

On the future of precision oncology, though precision cancer medicines have demonstrated success in treating some tumors with specific characteristics, most patients do not have access to such precision medicines. Rulten et al. (2023) recommend that future clinical research focus on:

• the discovery of new actionable disease characteristics
• rapid, accurate, and comprehensive diagnosis of complex phenotypes
• novel clinical trial designs with improved response rates
• widespread access to novel targeted therapies for all patients globally.

Research has also been conducted in other therapeutic areas, e.g., on autoimmune illnesses and the use of advanced technologies (e.g., autoantibody profiling, genomic analysis, proteomics, miRNA analysis, and metabolomics) to identify potential CDx to improve rheumatoid arthritis (RA) patient outcomes.

Targeted therapy

With a focus on CDx and predictive biomarkers for mesenchymal epithelial transition (MET)-targeted therapy, Jørgensen & Mollerup (2022) reported that there was only one MET-targeted drug (capmatinib) approved with a CDx assay. The authors proposed that one of the reasons relatively few drugs targeting MET for cancer have obtained regulatory approval is the lack of effective predictive biomarkers for patient population selection. Studying MET amplification in patients with metastatic EFGR-mutated NSCLC, Urbanska et al. (2023) observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing (NGS) should be used together as they possess different sensitivities and complement.

Regulatory approval

If a CDx has poor diagnostic performance or is inadequately validated, treatment prediction based on the CDx’s diagnostic results is impossible. Given the important role of CDx in clinical research and treatment, regulators are putting stringent regulations and requirements for clinical data in place. New regulation of IVD medical devices in the European Union (EU), for example, came into full effect in May 2022.

With a focus on the impact of co-development of CDx and oncology drug development in Japan, Tanaka et al. (2022) analyzed approval lags and drug development periods of recently approved cases. The authors concluded that using CDx from the early development phase and the global development strategy could positively impact the drug development period.

Economic efficiency

Liu et al. (2023) conducted a systematic review to identify, summarize, and critique cost-effectiveness evidence for using biomarker-driven and imaging-based CDx for cancer treatment. Of the 12 papers meeting the eligibility criteria, ten reported that implementing biomarker-driven, imaging-based CDx was cost-effective, cost-saving, or dominant (cost saving and more effective). The authors concluded, however, that there was room for improvement regarding the quantity and quality of economic evaluations on such CDx.

Research has also been conducted to assess the value of comprehensive genomic profiling (CGP) in oncology as a universal CDx for targeted therapies. Tarride et al. (2022) studied data from academic and policy literature. They interviewed stakeholders (e.g., health economists, payers, clinicians) of countries using incremental cost-effectiveness ratios as part of health technology assessment (HTA). The authors found that the evaluation of the overall value of CGP is limited by the current models of HTA.

Conclusion

CDx plays a role in clinical practice, working with therapeutics to improve patient outcomes and reduce economic burden. In addition, CDx plays an important role in advancing clinical research, facilitating the development of precision medicines and targeted therapies while accelerating drug approval to ultimately speed up patient access to ground-breaking scientific therapeutics.

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