Understanding biomarker validation, qualification challenges

What are biomarkers?

The FDA defines biomarkers as molecular, histologic, radiographic or physiologic characteristics that are measured "as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions."

There are seven biomarker categories:

• Susceptibility or risk.
• Diagnostic.
• Monitoring.
• Prognostic.
• Predictive.
• Pharmacodynamic or response.
• Safety.

Before a biomarker is actively used in the healthcare landscape, it goes through three primary phases: discovery, validation and qualification.

The discovery phase is focused on actually identifying the biomarkers, which can happen in multiple different ways. Biomarkers can be discovered accidentally or intentionally, with discovery strategies ranging from biological research to data analysis, targeted clinical trials, data mining and beyond.

Once a biomarker has been discovered -- regardless of the method -- it must be validated before it can be used in clinical settings. The validation phase confirms the biomarker's reliability and relevance in a clinical context, clarifying whether it can consistently be used to draw biological insights. There are two primary kinds of validation: analytical and clinical validation. Analytical validation tests for accuracy, precision, sensitivity, specificity and reproducibility, while clinical validation is used to assess a biomarker's ability to predict clinical outcomes.

Through validation, researchers can prove that a biomarker is reliable and relevant in a particular clinical landscape, allowing the biomarker to move from the validation phase to the qualification phase.

Qualification is focused on the regulatory approval process and implementing the biomarkers in clinical use. Throughout this process, researchers and sponsors must engage with regulatory bodies, such as the FDA, develop standard operating procedures, demonstrate the biomarker's clinical utility and monitor its performance in real-world settings.

Each phase plays a critical role in getting the biomarker to clinical settings and ensuring the benefits and safety of its use.

Challenges in biomarker validation, qualification

Many challenges can arise because the process of getting biomarkers from discovery to qualification is rather intense. Although discovery poses its own set of challenges and requires intensive research, this article will focus on the challenges of validation and qualification once a biomarker has already been discovered.

Reproducibility

One of the primary challenges in biomarker validation and qualification is reproducibility. Once a biomarker has been identified or discovered in a study, researchers must prove that it can consistently be used as a biological indicator.

According to a 2023 article in Cancers, "the irreproducibility of biomarkers and discrepancies of reported markers have remained a major roadblock to clinical implementation, demanding the investigation of contributing factors and the development of standardized biomarker discovery pipelines."

Biomarker assays that yield different results in various settings or across different experiments can result in inconsistent findings, which underscores the importance of developing assays that can be reproduced, proving the biomarker's credibility.

Standardization

Standardization challenges go hand in hand with reproducibility challenges. There are no standardized protocols for measuring and reporting biomarkers, which can present a challenge for researchers during validation and qualification.

A lack of standardization can make it difficult to compare data across studies and make conclusions about a particular biomarker. A lack of standardization can result in unreliable and unapplicable biomarkers.

Analytical validation

The analytical validation process is critical for evaluating biomarkers' sensitivity, specificity, and reproducibility. Although it can be time-consuming and costly, without it, researchers might find that biomarkers are used inaccurately, resulting in misdiagnosis or incorrect treatment.

Clinical relevance

Proving a biomarker's clinical relevance is a major hurdle in validation and qualification. Even if a biomarker is reproducible and measurable, it is not useful if researchers cannot prove its clinical relevance. Without proven clinical significance, biomarkers cannot offer meaningful insights into patient care, making them useless in practical applications.

Population diversity

Another challenge of biomarker validation and qualification is ensuring that the biomarkers are valid and accurate across a diverse population. Some biomarkers might perform significantly differently depending on different genetic, environmental, and lifestyle factors.

When validating and qualifying biomarkers, researchers must consider how these different factors can impact performance. Ideally, biomarkers should apply to all populations or across an entire disease population. However, if a biomarker is only validated across one population, its applicability is limited. Generalizing a biomarker that has not been validated for the entire patient population across a diverse population can also perpetuate health disparities.

Regulatory hurdles

Regulatory hurdles pose a significant threat throughout the qualification process. Regulatory agencies, rightfully, have rather strict protocols for biomarker qualification. Researchers and sponsors must adhere to these requirements to qualify their biomarkers, at which point they can be applied in clinical settings.

Beyond the initial regulatory hurdles, varying requirements across different regulatory agencies pose an even bigger challenge.

Longitudinal studies, economic considerations

One major challenge associated with biomarker validation and qualification is time. Validating biomarkers can require longitudinal studies that span years.

Although longitudinal studies are extremely beneficial, as they provide valuable insights and allow researchers to validate biomarkers across changes in patient health, treatment regimens and other variables, they can also be extremely costly.

Funding research for diverse populations over an extended period of time requires personnel, resources and tools. These economic barriers can pose significant challenges for researchers and might limit biomarker validation and qualification.

Integration challenges

For biomarker research to be worth the investment, biomarkers must be implemented into clinical practice. However, implementing new tools into clinical workflows can be challenging and requires collaboration and cooperation between several stakeholders, including researchers, providers and regulatory organizations.

The inability to easily integrate biomarkers into clinical practice might limit their benefits and result in underutilization.

Researchers working in the biomarker landscape must consider how these barriers might impact their research processes and findings. Understanding the challenges and limitations ahead of the validation and qualification process can help researchers anticipate challenges and develop practices to address these concerns.

Veronica Salib has covered news related to the pharmaceutical and life sciences industry since 2022.