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Table 3 Biomarker example types organized by biological level and compared for pathophysiologic level

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

Biomarker Type Pathophysiologic Process or Stage General Examples Specific Examples Pros Cons
Genetic marker 1° Cause Presence of a gene mutation CF mutations Measure presence of gene Not a function
RNA/gene expression 1° pathophysiologic Expression of aberrant RNA Friedrich’s ataxia Direct impact on gene expression Unclear about downstream effect
RNA splicing error Fragile X
Presence of new gene expression
Enzyme or protein level 1° pathophysiologic Enzyme activity in tissue Alpha-1-antitrypsin Direct measure of active compound Difficult to verify tissue effect
Protein in circulation
Biochemical 1° pathophysiologic Blood level of an accumulating metabolite due to a 1° block Phenylalanine in PKU Directly toxic compound or active compound Not a measure of tissue effect
Decrease in level of critical needed biochemical BH4 in BH4 deficiency
Secondary Biochemical 2° pathophysiologic Increase in secondary metabolite that is toxic or part of pathophysiology but not from original defect Succinyl-lactone in tyrosinemia I Directly measure of toxic effector Cannot always measure downstream toxicity
Homogentisic acid in alkaptonuria
Biopsy 2° pathophysiologic Presence of abnormal cells or marker GL3 granules in Fabry Direct measure of disease or absence of protein Variability of biopsies, representative sampling, variable assay methods
Pathological change in structure Dystrophin in Duchenne
Ex vivo explant 2° pathophysiologic Evaluate a cell removed from the patient for a phenotype or function CGD/y-interferon None Failed : questionable validity of an ex vivo assessment
X-ray/Imaging 2° pathophysiologic Bone structure X-ray ricket score Bone structure is nature of disease X-ray does not show function exactly
Presence of abnormal lesions
Change in size
Visual appearance like fundoscopy
Clinical Physiology tests 1° clinical effect Tests used in clinical evaluations of clinical conditions dependent primarily on a single tissue/organ FVC in CF Measure of a physical function that is directly relevant Not strictly a clinical outcome and hard to gauge size of effect with clinical outcome
EMG, EKG, NCV, BAER, hand held dynamometry Muscle strength in DMD or HIBM
Clinical function 2° clinical effect or intermediate clinical measure Tests that study integrated multiple body systems/organs, Pulmonary function tests, sleep apnea, muscle function 6 min walk test Measure of a patient’s function Need to interpret magnitude of change for relevance to patient
Walking speed
  1. The table provides examples of different types of specimens that might be obtained from a patient or featured measured in a patient and relates these examples to their pathophysiologic stage. The goal is to highlight the type of measures and relate these measures to the cause of disease and those steps that are further downstream. Examples for the endpoint measure in patients with specific diseases are provided to highlight the pros and cons of different types of biomarkers.