Aki Morikawa and Ayca Gucalp
Biomarker Definition
A characteristic that is objectively measured & evaluated as an indicator of nl biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (NIH Biomarkers Definitions Working Group: Clin Pharm Thera 2001;69:89)
Types of Biomarker
Prognostic: ↑ risks of dz or dz progression; usually independent of interventions/drugs (as opposed to predictive biomarker); useful in assessing chance of specified outcomes
Predictive: Predicts response to an intervention or risk of tox; useful in selecting pts for tx & for trials
Mechanistic or Biologic: Reflects biologic process; useful for post-tx monitoring or measurement of tumor burden
Surrogate end point: A substitute for clinical outcome such as RR, DFS, or other measures that can predict clinical benefit; often used as a correlate of OS; allow rapid drug development & approval
PK: “How the body affects the drug”; study of the transport & metabolism of administered drugs, including absorption, distribution, tissue localization, biotransformation, & excretion
PD: “How the drug affects the body”; indicator of drug/intervention effects on specific molecular targets or pathways; may be used as a proof of mechanism, disease monitoring, & post-tx evaluations
Types of Biomarker and Examples
Steps in Biomarker Development
Identify marker of clinical utility: Evaluate metabolic, biochemical, gene, & molecular targets or pathways in animal models & preclinical studies
Evaluate analytical validity of assay: Accuracy, precision, & reproducibility; appropriate specimen collection & handling & technical issues; if used to make individual pt decisions -> must be done in a CLIA certified labs (CLIA regulations: http://www.cdc.gov/clia/regs/)
Clinical validity & utility assessment: Phase I, II, & III clinical trials; internal validation & external validation; assess reproducibility of the result; provide a statistical design to assess clinical correlations
discovery (may be done in small sample size to discover potential markers)
training (test previously identified markers in a small independent cohort)
validation set (test marker in larger population independent from training set to provide supportive evidence for clinical use)
Figure 2-1 Biomarker Development Flow Chart
Biomarkers in Drug Development
Evaluating activity in preclinical studies
Prioritize & validate potential candidate drugs & interventions for further clinical studies
Evaluate safety in preclinical & clinical studies
Evaluate dose–response, optimal regimen, & dose; use of MED & OBD assessments in addition to MTD in early trials; potential for less exposure of tox
Determine metabolism in different subpopulations
Use as a surrogate end point to accelerate development & approval of new drugs & interventions
Stratify study population by selecting appropriate subpopulation for clinical trials of targeted agents