Biomarkers have the potential to serve as valuable tools throughout the entire drug development process, but the utility ultimately depends on the refinement, implementation, and qualification of the biomarker. Before reaching a stage where they can provide value, biomarkers must first undergo rigorous testing and validation (figure 1).

Novel biomarker discovery relies on different methodologies, such as imaging and biochemical techniques. The early stages of fluid biomarker discovery usually involve a large screening of analytes in few samples and is successively escalated to few analytes in more samples, as the proof of concept develops.


Figure 1. Schematic overview of the road from biomarker discovery to clinical utilization. Biomarkers undergo thorough technical and analytical scrutiny during development before clinical qualification and utilization. The highlighted parameters reflect the CLSI guidelines for assay development and validation.

As development progresses, the clinical specificity and sensitivity of the biomarker is continuously evaluated. A great point to consider in this regard is the value of biobanking for retrospective analyses and potential discovery of novel biomarkers. During the development process, it is important to consider pre-analytical factors which can influence the process and integrity of the biomarker. These include status of the patient from which the sample is derived, biospecimen collection, handling and storage, and attention to freeze-thaw cycles of the sample.

Analytical validation is characterized by analysis of the biomarker assay performance with the goal of ensuring a repeatable measurement with low variance and good sensitivity and specificity. Multiple parameters are assessed during this phase, including selectivity, accuracy, precision, recovery, sensitivity, reproducibility, and stability. Depending on the intended use of the biomarker assay certain standards must be met, such as the Clinical Laboratory Improvement Amendments (CLIA) for assays to be used for testing human samples.

A biomarker validation according to the Clinical Laboratory and Standards Institute (CLSI) guidelines can further reduce the risk of a technical or analytical failure, thus increasing the utility of the biomarker assay, and is required for qualification and approval of the biomarker assay.

Clinical qualification is based on evidence generated using the biomarker assay in a clinical setting, connecting the biomarker to biological and clinical endpoints. The Center for Drug Evaluation and Research (CDER) within the FDA has established formal guidance documents for the process of biomarker qualification, providing a framework aimed at regulatory approval for the use in drug development. Reaching regulatory approval, the biomarker assay can be officially used within the stated COU for assisting in decision making related to drug development.

Clinical utilization is assessed by evaluating the performance of the biomarker assay in its stated COU, and includes procedures such as disease diagnosis, monitoring, treatment selection and prognosis. Formal qualification is not necessarily needed for a biomarker to provide clinical utility, but significantly enhances the clinical utility. Particularly when using the biomarker in the context of drug development and is required to support regulatory approval of a drug or when used as a surrogate endpoint.

It is important to consider that most biomarkers often do not make it through discovery, validation and implementation due to various reasons. Biomarker development may fail both because of technical and hypothesis-driven failures. The cost of bringing a biomarker to the market is extremely high, and often needs a co-development process including a drug.

Many drugs unfortunately fail in development due to lack of demonstrating efficacy, and so do biomarker candidates. In addition, changing clinical practice is a big hurdle, which takes many years, thus the return-of-investment from investing in both biomarkers and drug development is often lacking for biomarkers with limited investments.

Additionally, it is easier to do biomarker discovery with a bigger platform such as SomaScan and Olink, but the investment taken from discovery to refinement over many studies, with CLSI technical validation along the way (figure 1), is long and costly. Moreover, submission to regulatory agencies in relation to formal qualification of biomarkers is long, expensive and requires substantial data to be generated, which further complicates the possibilities for smaller companies and research groups.

Please don't hesitate to contact us if you have any questions or other inquiries.

Are you interested in learning more about Nordic Bioscience?
Enter your information in the form and a representative will contact you shortly.

By submitting this form you agree to our terms and conditions.