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Clinical biomarkers in drug discovery and development

Nature Reviews Drug Discovery volume 2, pages 566–580 (2003)Cite this article

Abstract

Biomarkers enable the characterization of patient populations and quantitation of the extent to which new drugs reach intended targets, alter proposed pathophysiological mechanisms and achieve clinical outcomes. In genomics, the biomarker challenge is to identify unique molecular signatures in complex biological mixtures that can be unambiguously correlated to biological events in order to validate novel drug targets and predict drug response. Biomarkers can stratify patient populations or quantify drug benefit in primary prevention or disease-modification studies in poorly served areas such as neurodegeneration and cancer. Clinically useful biomarkers are required to inform regulatory and therapeutic decision making regarding candidate drugs and their indications in order to help bring new medicines to the right patients faster than they are today.

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Figure 1: Reasons for attrition.
Figure 2: Biomarker categories: target, mechanism and clinical.
Figure 3: Reasons surrogate endpoints 'fail'.
Figure 4: Correlation of brain iron staining and T2 mapping.
Figure 5: Computed tomography lung nodule.
Figure 6: Whole-body PET-CT.
Figure 7: NK1 receptor occupancy required for efficacy.
Figure 8: Positron emission tomography across species.
Figure 9: In vivo response depends on haplotype pair.
Figure 10: Metabonomics array.

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Authors and Affiliations

  1. Pharmacia, Peapack, New Jersey, 07977, USA

    Richard Frank

  2. Merck & Co, 770 Sumney Town Pike, West Point, Pennsylvania, 19486, USA

    Richard Hargreaves

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Supplementary information

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Related links

DATABASES

LocusLink

α7 nicotinic acetylecholine receptor

CYP1A2

CYP2D6

ERBB2

FMO3

NK

Cancer.gov

Breast cancer

melanoma

Online Mendelain Inheritance in Man

Alzheimer's disease

multiple sclerosis

osteoarthritis

Parkinson's disease

Tangier disease

FURTHER INFORMATION

Center for Drug Evaluation and Research: Guidance for Screening INDs

National Institute of Mental Health Proposal for Treatment Units for Research on Neurocognition and Schizophrenia

American Association of Clinical Endocrinologists

Application of Genomics to Mechanism-based Risk Assessment

Biomakers and Surrogate Endpoints Conference

Genomics glossary

Gastrointestinal Drugs Advisory Committee

Guidance for Industry

Microsdosing Guidance

National Institute on Aging Alzheimer's disease neuroimaging initiative

National Institute of Mental Health Treatment Development Initiative

Osteoarthritis biomarker initiative

Osteoarthritis imaging initiative

Pharmacogenomics

Principles of software validation

Technical Committee of Application of Genomics to Mechanism-based Risk Assessment

Society for Non-Invasive Imaging in Drug Development

Standards for Reporting of Diagnostic Accuracy

Glossary

BIOLOGICAL MARKER (BIOMARKER)

A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

SURROGATE ENDPOINT

A biomarker intended to substitute for a clinical endpoint. A clinical investigator uses epidemiologic, therapeutic, pathophysiologic, or other scientific evidence to select a surrogate endpoint that is expected to predict clinical benefit, harm, or lack of benefit or harm.

CLINICAL ENDPOINT

A characteristic or variable that reflects how a patient feels or functions, or how long a patient survives.

SINGLE-NUCLEOTIDE POLYMORPHISM

(SNP). A variant in a single base pair which can occur in any region of the gene including promoters, introns, exons, splice junctions or even untranslated regions.

MULTI-DRUG RESISTANCE

(MDR). A set of proteins which oppose tumour uptake of chemotherapeutic drugs by transporting them back into the bloodstream.

DRUSEN

Small yellowish protein–lipid deposits in the retina that develop in the early stages of dry (atrophic) macular degeneration.

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Frank, R., Hargreaves, R. Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2, 566–580 (2003). https://doi.org/10.1038/nrd1130

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