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

From: Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints

Type of Consideration Criteria for establishing the scientific framework for qualifying biomarkers
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
  1. This table lists the five primary considerations in establishing the scientific framework for qualifying biomarkers as surrogate primary endpoints with supporting points for each.