Table 1 Considerations in establishing the scientific framework for qualifying biomarkers as surrogate primary endpoints

Disease considerations

• Clear disease cause

• Disease pathophysiology known

• No alternative disease pathogenesis pathway

Drug considerations

• Clear structure and identity

• Direct and understood mechanism of action

• Demonstrated specific pharmacological action

• Demonstrated relevant absorption, distribution, metabolism, and excretion (ADME) in models

Biomarker considerations

• Directly related to pathophysiologic pathway

• Changes are sensitive and specific to changes in clinical disease pathophysiology

• Demonstrates biological stability

• Validated or qualified assay methodology exists for biomarker measurement

• Clinical physiological measures, also called clinical intermediate endpoints, should be considered predictive biomarkers when directly relevant to major clinical problem

Preclinical considerations

• Develop models relevant to disease pathophysiology

• Presence of a broad and dynamic dose–response relationship

• Compartment reflects disease tissue compartment

• Changes predict clinical changes in models

Clinical data considerations

• Predicts clinical severity or disease progression rate

• Sufficient breadth in detecting disease and its range in severity

• Shows predictive value for other, similar diseases