A biomarker intended for general use in drug development can be granted qualification by the Center for Drug Evaluation and Research (CDER) through the Biomarker Qualification Program, leading to the establishment of a drug development tool that holds applicability within a specific COU during the drug development process.

While the Biomarker Qualification Program is responsible for endorsing the specific biomarker (the designated analyte), it's crucial to note that a biomarker cannot attain qualification without an accurate and dependable measurement method, and the qualification solely is for drug development and not real-life diagnostic use.

The process of biomarker qualification is a collaborative endeavor where regulatory agency personnel collaborate with the requester to guide the development of the biomarker. Due to the arduous nature of advancing a biomarker towards qualification and the requirement for robust evidence from multiple trials to support a COU, various parties often collaborate within working groups or consortia to achieve biomarker qualification.

This collaborative approach leverages shared resources, alleviates the individual burden on collaborators, and grants the group access to valuable insights that may not be accessible independently. This process was recently review by the LITMUS consortium, disclosing the full feedback from this process from both EMA and FDA, enabling other researchers to follow and use this information, to allow addition and faster Submissions.

Biomarker qualification, as mandated by the 21st Century Cures Act, follows a three-stage submission process to develop a biomarker for regulatory purposes. This process includes the submission of a LOI, a qualification plan, and a comprehensive full qualification package.

If the FDA determines the documentation submitted at each of these stages as acceptable, a communication is conveyed to the requester through a letter encompassing feedback and recommendations for further advancing the biomarker's development. This iterative process allows requesters to collaborate with the CDER in addressing various facets of biomarker development.

To facilitate and enhance the likelihood of successful biomarker qualification, both the FDA and EMA have issued documents outlining an evidentiary framework and essential considerations. This framework is integral to the successful qualification of biomarkers. The FDA's evidentiary framework (figure 1), encompasses essential components such as the 'needs assessment', 'context of use', and a 'benefit-risk analysis'.

 

Figure 1. Evidentiary framework for biomarker qualification. The evidentiary framework for biomarker qualification has been outlined for the FDA, which covers the key items to address before moving forward with the biomarker qualification. These items are ‘needs assessment’, ‘context of use’, and a ‘benefit-risk analysis’. Based on this, the requestor determines the level of evidence required for a biomarker to be qualified.

These components guide the requester in determining the level of evidence required for the qualification of a biomarker. For instance, biomarkers associated with high-risk scenarios (e.g., exclusive enrollment of patients exceeding a threshold in a trial or clinical decision-making at the patient level) or those pivotal in definitive regulatory decisions (e.g., accelerated approval, full approval, or informing labeling) necessitate robust regulatory scrutiny and correspondingly extensive evidence to support their qualification. In contrast, biomarkers linked to low-risk situations, or those employed as exploratory markers (e.g., stratifying patients within a clinical trial), require relatively lower levels of evidence for qualification.

Surrogate endpoints, requiring the highest level of evidence, are markers anticipated to predict clinical benefit without being direct measures of it. Their qualification holds the potential to expedite trial durations, allowing quicker assessment of benefit-risk profiles for experimental interventions. At the other end of the spectrum are prognostic biomarkers, which require less evidence to support their potential use.

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