Biomarker Regulatory Considerations

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’.

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.