Pocket Oncology (Pocket Notebook Series), 1st Ed.

BIOMARKER DEVELOPMENT

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