This report focuses on disease-related biomarkers, those related to disease screening, prognosis, and stratification—more specifically, disease-related molecular biomarkers. Insight Pharma, Disease Related Biomarkers: Their Potential in Patient Screening, Prognosis and Stratification, 2007

Applications  Map: Finding guide to terms in these glossaries  Site Map
Related glossaries include Genetic & genomic testing   Metabolic profiling    Molecular Imaging,  Pharmacogenomics & Toxicogenomics,  SNPs & other Genetic Variations,

accessible biomarkers: A biomarker that can be obtained in a minimally invasive manner, typically from blood, urine or saliva.

Google = about 42 Oct. 25, 2004, about 78 Oct. 3, 2005

antecedent biomarkers: See under biological markers 

Google = about 37 Oct. 25, 2004, about 207 Oct. 3, 2005

biochemical biomarkers:  Biochemical biomarkers have long contributed to the assessment of risk and benefits in cancer, and routine clinical assays are available.  Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003 

Google = about 454 Nov. 9, 2004, about 539 Oct. 3, 2005

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. Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations.  http://www.fda.gov/cber/gdlns/pharmdtasub.pdf  

biological markers:  Measurable and quantifiable biological parameters (e.g. specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health - and physiology related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. MeSH, 1989 

 1. Parameter that can be used to identify a toxic effect in an individual organism and can be used in extrapolation between species. 2. Indicator signalling an event or condition in a biological system or sample and giving a measure of exposure, effect, or susceptibility.  [IUPAC Tox] 

Biological markers can reflect a variety of disease characteristics, including the level of exposure to an environmental or genetic trigger, an element of the disease process itself, an intermediate stage between exposure and disease onset, or an independent factor associated with the disease state but not causative of pathogenesis. Depending on the specific characteristic, biomarkers can be used to identify the risk of developing an illness (antecedent biomarkers), aid in identifying disease (diagnostic biomarkers), or predict future disease course, including response to therapy (prognostic biomarkers). Antecedent Biomarkers in Alzheimer's Disease, Alzheimers Research Forum, 2003  http://www.alzforum.org/res/enab/workshops/biomarkers.asp 

Google = about 10,900 Aug. 6, 2002; about 24,800 Aug. 18, 2003; about 84,000 Oct. 25, 2004, about 904,000 Oct. 3, 2005

Related/synonymous? terms: biomarkers, genetic markers, protein biomarkers, surrogate markers; Broader term: markers  Narrower term: genomic biomarkers

biological tumor markers: Cancer genomics glossary

Google = about 30 Aug. 6, 2002; about 59 Aug. 18, 2003; about 194 Oct. 25, 2004; about 275 Oct. 11, 2005

biomarker analytes: DNA, gene expression profiles, protein[s], protein expression, metabolite[s], cells or combinations of these can constitute biomarkers.

Google = about 15 Oct. 25, 2004, about 30 Oct. 3, 2005

biomarker discovery: The latest technologies in genomic, proteomic and metabolomic profiling; approaches and case studies to biomarker validation and translation; use of biomarkers in drug safety assessment; as well as biomarker applications in drug development, diagnostics, and pharmacogenomics. Biomarker Discovery Summit: Bridging the Silos in Biomarker Discovery and Validation Sept 17-19, 2007 • Philadelphia, Pennsylvania

Narrower terms: genetic biomarkers, genomic biomarkers, protein biomarkers, proteomic biomarkers

biomarker qualification: See under biomarker validation

biomarker validation: An important distinction is between biomarker validation and qualification, where validation is the process of assessing the assay or measurement performance characteristics and qualification is evidentiary process of linking a biomarker with biology and clinical endpoints.  J. Wagner, Merck, Asilomar Conference on Biomarkers Discovery and Validation, Oct. 14-18,  2004 http://bigdaddy.scripps.edu/darlene/Asilomar/pages/abstracts/jwagner.htm 

See also validated biomarkers

biomarkers:  Anatomic, physiologic, biochemical, or molecular parameters associated with the presence and severity of specific disease states. Biomarkers are detectable and measurable by a variety of methods including physical examination, laboratory assays and medical imaging.   Massachusetts General Hospital, Center for Biomarkers in Imaging, 2004 http://www.biomarkers.org/NewFiles/faqs/definition.html#Anchor-What-35882 

A biological process or biochemical indicator that precedes the development of disease and is usually indicative of the progression of disease. May be used to measure the effects of treatment. David Nathan, Diabetes Mellitus 2004, Biomarkers and the Development of New Therapeutics and Diagnostics,  FDA/NIH Joint Symposium, May 13, 2004 http://www.niddk.nih.gov/fund/other/FDA-NIH/Nathan.pdf 

Biomarkers may be any parameter of a patient that can be measured, for example, mRNA expression profiles, proteins, proteomic patterns, lipids, imaging methods, or electrical signals. The best biomarkers are accurate, relatively noninvasive and easy-to-perform tests that can be done at the bedside or in the outpatient setting. These tests involve a blood or spot urine specimen, can be measured serially, and have a fast turnaround. In the past, most efforts had focused on discovering tissue and urinary biomarkers. However, there has been a recent shift to finding serum biomarkers (11), with new methods and technologies making this more practical. Stephen M. Hewitt^*, James Dear and Robert A. Star, Discovery of Protein Biomarkers for Renal Diseases, J Am Soc Nephrology 15:1677-1689, 2004  http://jasn.asnjournals.org/cgi/content/full/15/7/1677 

A characteristic that is measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses. M. Danhof, Meeting Report, Markers of pharmacological and toxocological action, BioMedCentral, 2001  http://www.biomedcentral.com/abstracts/CRP/1/023/ 

Track 1: Biomarkers in Early Drug Development. Track 2: Biomarkers in Clinical Development, Track 3: Biomarkers for Molecular Diagnostics, Track 4: Biomarker Assay Development, Track 5: Toxicity Biomarkers, Pre-Conference Events: Executive Summit: Implementing a Biomarker Strategy for Better Decision Making, Tutorial: Biomarker Assay Development and Validation, Workshop: microRNA as Biomarkers, Workshop: Cancer Biomarkers Biomarker World Congress May 19-21, 2008, Philadelphia PA

A comprehensive program, covering all aspects of biomarker translation and implementation in the clinic. Case studies in all areas of biomarker research spanning the pharmaceutical and diagnostic pipeline, including safety and efficacy assessment in drug discovery/development, biomarker translation from pre-clinical to clinical studies, biomarker validation and utility in clinical trials, and biomarker assay development and validation. Biomarker Europe Nov 5-6 2007 Vienna Austria 

Google = about 70,300 Aug. 6, 2002; about 182,000 Aug. 18, 2003, about 430,000 Oct. 25, 2004, about 3,960,000 Oct. 3, 2005; about 4,810,000 Nov 14. 2006

Related/synonymous? terms:  biological markers, genetic markers, surrogate markers; Broader term: markers

Biomarkers Consortium: A public-private biomedical research partnership of the Foundation for the National Institutes of Health, Inc. that involves a variety of public and private stakeholders including the National Institutes of Health (NIH); Food and Drug Administration (FDA); Centers for Medicare & Medicaid Services (CMS); the pharmaceutical, biotechnology, diagnostics, and medical device industries; non-profit organizations and associations; and advocacy groups. http://www.biomarkersconsortium.org

biosignatures: Analyzing patterns of protein expression from tissues or fluids over the course of disease progression could reveal proteome- level "biosignatures" indicative of specific disease status. Such "biosignatures" may be used extensively in 21st century medical diagnostics. Similarly, analyses of protein profiles before and after pharmacological treatments could provide vital clues regarding drug effectiveness and toxicity. In addition, particular "biosignatures" may be used to customize therapeutic strategies for individual patients. [National Heart, Lung, and Blood Institute, Proteomics Initiative, Sept. 5, 2001, RFP/BAA: BAA-02-04] http://grants1.nih.gov/grants/guide/notice-files/NOT-HL-02-004.html

Google = about 879 Aug. 6, 2002; about 1,740 Aug. 18, 2003; about 4,110 Oct. 25, 2004, about 34,500 Oct. 3, 2005; about 68,700 Nov 14, 2006

Related term: protein biomarkers

bridging biomarkers: Biomarkers of cellular injury that can link laboratory findings directly to human outcomes.  A biomarker for a given analyte or set of analytes that can be applied in both a pre- clinical and clinical setting.

Google = about 65 Oct. 25, 2004, about 154 Oct. 3, 2005; about 214 Nov 14, 2006

CDISC Clinical Data Interchange Standards Consortium: Drug Approvals glossary

cancer biomarkers: Cancer genomics glossary

Google = about 4,750 Oct. 25, 2004; about 61,200 Oct. 11, 2005; about 108,000 Nov 14, 2006

cellular biomarkers: Fundamental to many tissue- engineered devices are problems of inflammation associated with how biological cells respond to a given device when inserted into the body. ... To assure that tissue- engineered materials are free of molecular changes that could occur during the in vitro development phase, cellular biomarkers are being identified that can be used during the manufacturing process. H. Rodriguez, Cellular Biomarkers Used to Detect Damage in Tissue- Engineered Medical Products, Society for Biomaterials,  May 01, 2002, Technipubs, Recent Publications by NIST authors  http://ois.nist.gov/nistpubs/technipubs/recent/search.cfm?dbibid=11200 

Google = about 469 Oct. 25, 2004; about 544 Oct. 11, 2005; about 766 Nov 14, 2006

chemical biomarkers:  Chemical biomarkers released by the host in response to invasion and infection could provide a target for antibody arrays, mass spectrometry, and other analytical techniques to diagnose infection. In spite of these advances, general research into the biochemistry of agents and the rapid identification of pathogenicity of agents is still needed. National Security and Homeland Defense: Challenges for the Chemical Sciences in the 21st Century, National Academies Press, 2003 http://www.nap.edu/nap-cgi/morehits.cgi?display=text&isbn=0309085047&tm... 

Google = about 136 Aug. 6, 2002; about 230 Aug. 18, 2003l; about 319 Sept. 2, 2004; about 432 Oct. 11, 2005; about 718 Nov 14, 2006

clinical biomarkers: As biomarkers are making their way into clinical trials, researchers and clinicians are facing challenges in modifying trial design and defining the right control population, validating biomarker assays from the biological and analytical perspective, and using biomarker data as a guideline for decision-making. The Clinical Biomarkers Summit will address biomarker translation from pre-clinical to clinical studies and a variety of biomarker applications in clinical trials, including patient selection, monitoring clinical efficacy and safety, and clinical pharmacology. The Summit also addresses the bridging gap between the pharmaceutical and diagnostics industries and the potential of pharmacogenomics and pharmacodiagnostics. Specific case studies of leveraging biomarkers in accelerating and streamlining clinical trials will offer you a "state-of-the-field" status report. Clinical Biomarkers Summit March 19-21, 2007 • Coronado, California

This report focuses on disease-related biomarkers, those related to disease screening, prognosis, and stratification — more specifically, disease-related molecular biomarkers. Insight Pharma, Disease Related Biomarkers: Their Potential in Patient Screening, Prognosis and Stratification, 2007 http://www.insightpharmareports.com/reports/2007/83_Disease_Biomarkers/overview.asp 

Biomarkers can be influential in every phase of drug development, from drug discovery and preclinical evaluations through each phase of clinical trials and into post- marketing studies. Biomarkers can predict a patient’s response to a compound, act as a surrogate endpoint, and aid in making efficacious and cost- saving decisions or terminating drug entities more quickly during the research process. Patient enrichment strategies are using biomarkers to identify certain patient populations that are more likely to respond to the drug therapy or to avoid specific adverse events.  CHA Cambridge Healthtech Advisors, Biomarkers in Clinical Development: Implications for Personalized Medicine and Streamlining R&D report, 2005

Google = about 22,000 Nov 14, 2006; about 29,300 June 25, 2007

clinical endpoint: A characteristic or variable that reflects how a patient feels, functions or survives. Biomarkers Definition Working Group, 1998, Gregory Downing, NIH Initiatives in Surrogate Endpoints and Endpoint Analysis,  Nonclinical Studies Subcommittee, Advisory Committee for Pharmaceutical Science presentation, 2000  http://www.fda.gov/ohrms/dockets/ac/00/slides/3593S1_03_downing.ppt 

clinical pharmacometabolomics:  The segregation of patient populations using small molecule biomarkers in clinical trials, adverse drug reaction, and drug efficacy evaluation.  Phenomenome Discoveries http://www.phenomenome.com/ 

Broader term: pharmacometabolomics

combination biomarkers: Biomarkers that are based on more than one category of analytes. (Alternatively: Integrative biomarkers, Systems biology biomarkers)

Google = about 22, Oct. 25, 2004; about 40 Oct. 11, 2005; about 55 Nov 14, 2006

Related/narrower terms: DNA markers, genetic biomarkers, genomic biomarkers, metabolic biomarkers, metabolite biomarkers,  metabolomic biomarkers, protein biomarkers, proteomic biomarkers

companion diagnostics biomarkers: Pharmacodiagnostics: Prospects for Companion Diagnostics, Development of Biomarker-based Diagnostics, Expression Profiles for Disease Staging and Response Prediction, Pre-Symptomatic Disease Detection, Biomarker Assay Development and Validation, “Fit-for-purpose” Analytical Validation, Expression Profile Analysis and Interpretation, Novel Diagnostic Platforms, Potential of Microarrays in Molecular Diagnostics, Microarray Data InterpretationBiomarkers for Molecular Diagnostics, Pharmacodiagnostics: Prospects for Companion Diagnostics, Development of Biomarker-based Diagnostics, Expression Profiles for Disease Staging and Response Prediction, Pre-Symptomatic Disease Detection, Biomarker Assay Development and Validation, “Fit-for-purpose” Analytical Validation, Expression Profile Analysis and Interpretation, Novel Diagnostic Platforms, Potential of Microarrays in Molecular Diagnostics, Microarray Data Interpretation.  Companion Diagnostics Clinical Biomarker Summit, March 29-31, 2006, Coronado CA

DNA marker:  A cloned chromosomal locus with allelic variation that can be followed directly by a DNA- based assay such as Southern blotting or PCR. [NHLBI]

Google = about  6,100 Aug. 6, 2002; about 10,900 Aug. 18, 2003; about 22,000 Sept. 2, 2004; about 389,000 Nov. 14, 2006

diagnostic biomarkers: May span a continuum from early to more advanced disease manifestations. May be used as synonymous with disease biomarkers. See also under biological biomarkers

Google = about 633 Oct. 25, 2004, about 25,700 Nov 14, 2006

Narrower terms: disease onset biomarkers, monitoring biomarkers, occurrence biomarker, staging biomarkers
Related terms: Molecular Medicine glossary: molecular diagnostics, molecular epidemiology

diagnostics: Molecular Medicine glossary

direct biomarkers: See under indirect biomarkers

Google = about 39 Oct. 11, 2005; about 85 Nov 14, 2006

disease biomarkers: The goal of this initiative is to validate biomarkers for well-defined human diseases of liver, kidney, urological tract, digestive and hematologic systems, and endocrine and metabolic disorders, diabetes and its complications, and obesity, for which there are no or very few biomarkers, or for which standard biomarkers are currently prohibitively invasive or expensive. New biomarkers will stimulate bench to bedside translation by providing measures of the biological effects of potential new treatments. The ideal biomarker can be measured in a minimally invasive way, can be measured repeatedly over time, identifies early stages of disease, is indicative of disease prognosis, and correlates well with progression and response to therapy. Especially of interest would be studies designed to test the validity of candidate biomarkers or new technologies to monitor candidate biomarkers in patient tissue samples or small groups of well-characterized patients. Development of disease biomarkers, NIH PA-05-098, Release Date: April 27, 2005 http://grants.nih.gov/grants/guide/pa-files/PA-05-098.html#PartI 

Biomarkers of disease: cover measurement of endogenous substances or parameters indicative of a disease process and the use of pharmacodynamic and genetic markers in evidence- based laboratory medicine and treatment (markers of efficacy). Biomarkers, Taylor & Francis, Aims & Scope http://www.tandf.co.uk/journals/titles/1354750x.asp 

disease markers: The journal publishes original research findings (and reviews solicited by the Editor) on the subject of the identification of markers associated with the disease processes whether or not they are an integral part of the pathological lesion. The disease markers may be a genetic host factor predisposing to the disease or the occurrence of cell-surface markers, enzymes or other components, either in altered forms, abnormal concentrations or with abnormal tissue distribution.  Disease Markers, Aims and Scope,  IOS Press http://www.iospress.nl/html/02780240.php 

Google = about 5,260 Aug. 18, 2003; about 15,600 Sept. 2, 2004, about 115,000 Oct. 3, 2005; about 47,200 Nov 14, 2006

Narrower terms: disease risk biomarkers, disease onset biomarkers, monitoring biomarkers, occurrence biomarkers, staging biomarkers

disease onset biomarkers:  Reports onset of disease, prior to clear symptomatic evidence. Identification of such biomarkers will be quite difficult, because confirmation of disease onset will occur later, but require access to earlier samples.

Google = about 5 Oct. 25, 2004, about 5, Oct. 3, 2005; about 7 Nov 14, 2006

disease risk biomarkers:  Typically based on DNA, in some cases disease occurrence is uncertain, in others timing of disease onset is uncertain.

Google = about 16 Oct. 25, 2004, about 42 Oct. 3, 2005; about 58 Nov 14, 2006

Related/synonymous? term: antecedent biomarkers

drug development biomarkers: Biomarkers offer actionable data for efficacy, MOA, safety, and pharmacology evaluation, leading to more informed lead selection. 

Google = about 134 Nov 14, 2006

Narrower terms: bridging biomarkers, efficacy biomarkers, exclusion biomarkers, inclusion biomarkers, safety biomarkers, target biomarkers, toxicity biomarkers

EST Expressed Sequence Tags: DNA glossary

efficacy biomarkers: In oncology, a special class of extensively evaluated biomarkers of efficacy (surrogate endpoints) that generally correlate with desired clinical outcomes can be used as a basis for corporate decisions as well as for gaining accelerated provisional regulatory approval of a drug. E. Floyd, TM McShane, Development and Use of Biomarkers in Oncology Drug Development, Toxicol Pathol. 32 (Supplement 1) 106- 115, 2004

A biomarker that reflects beneficial effect of a given treatment. (May be simply reversal of a disease biomarker.)

Google = about 142 Sept. 2, 2004; about 216 Oct. 11, 2005, 747 Nov 14, 2006

epigenetics: Genetic manipulation & disruption glossary

evidence-based pharmacodynamic markers:

Google = about 17 Nov 14, 2006

exclusion biomarkers: A biomarker that predicts that a given treatment will produce an adverse response.  Could be used to exclude patients from clinical trials. 

exploratory biomarkers: Biomarkers based on general exploratory or research information, such as broad gene expression screening, or collection of sera or tissue samples, and that has not reached the status of a probable valid biomarker. Insight pharma Reports, Biomarkers in Clinical Development: Implications for Personalized Medicine and Streamlining R&D report, 2005

exposure biomarkers: cover detection and measurement of internal exposure to drugs and other chemicals. Biomarkers, Taylor & Francis, Aims & Scope http://www.tandf.co.uk/journals/titles/1354750x.asp 

Google = about 23,900 Nov 14, 2006

genetic biomarkers: A single gene (DNA) for which a mutation, deletion, SNP or some other feature provides predictive value.

Google = about 680 Sept. 2, 2004; about 10,300 Oct. 11, 2005; about 18,700 Nov 14, 2006

genetic markers:  A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event MeSH, 1989

Consist of specific nucleotide patterns. [NHLBI] 

Google = about 40,200 Aug. 6, 2002; about 87,100 Aug. 18, 2003; about 142,000 Sept. 2, 2004; about 1,470,000 Oct. 11, 2005; about 1,200,000 Nov 14, 2006

Related term: ESTs Gene definitions UniGene (database) has marker information

genetic variation: SNPs & other genetic variations glossary

genomic biomarkers: Using genomic biomarkers in drug and diagnostic development and regulatory decision making is showing a lot of potential, but still requires more qualification and validation. We have identified two key application areas First, at the drug discovery stage, genomic biomarkers applied to compound profiling offer efficacy and toxicity data, allowing better decision making at earlier stages and reducing late-stage attrition. Second, in the clinical setting, genomic biomarkers have the promise in disease diagnosis/ prognosis; treatment, patient, or dose selection; and clinical safety and efficacy assessment. While, according to the FDA, approximately 10% of the approved drug labels contain pharmacogenomics information with biomarkers, the field of personalized medicine is still at its infancy. Genomic biomarkers: Discovery, Validation, and Applications in Drug and Diagnostic Development September 17-19, 2007 • Philadelphia, PA

A measurable DNA or RNA characteristic that is an indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other inventions.    could, for example, reflect: The expression of a gene, The function of a gene, The regulation of a gene ... does not include the measurement and characterisation of proteins or low molecular weight metabolite. DNA characteristics include, but are not limited to Single Nucleotide Polymorphisms (SNPs), Variability of short sequence repeats, DNA modification, e.g. methylation, Insertions, Deletions, Copy number variation, Cytogenetic rearrangements, e.g. translations, duplications, deletions or inversions.  RNA characteristics include, but are not limited to RNA sequence, RNA expression levels, RNA processing, e.g. splicing and editing, MicroRNA levels. E15 terminology in Pharmacogenomics, ICH Draft 2 (Revision 2), 2006 http://www.fda.gov/cder/guidance/7619dft.pdf 

A gene expression pattern (RNAs) that is able to discriminate or predict.

Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels, FDA, 2006 http://www.fda.gov/cder/genomics/genomic_biomarkers_table.htm 

Google = about 579 Sept. 2, 2004; about 9,280 Oct. 11, 2005, about 14,400 April 24, 2006, about 15,300 Nov 14, 2006; about 16,400 Apr 6, 2007

genotypic biomarkers: The cytochrome P450 (CYP) system of drug metabolising enzymes represents the best studied set of pharmaceutically important genotypic markers. Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003

Google = about 41 Oct. 11 2005, about 42 Nov 14, 2006

haplotype biomarkers: Because haplotypes include the linkage of multiple SNPs, they will generally occur at lower prevalence than individual gene variants, and the more SNPs involved in a haplotype, the narrower and more precisely defined will be the patient subgroups. Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003

"ideal" biomarkers:  Should have high sensitivity and specificity as well as high predictive value for disease, be easy to obtain through noninvasive procedures, and be easy to measure with precision and accuracy. Executive Summary, DIET, DNA METHYLATION PROCESSES AND HEALTH WORKSHOP, National Cancer Institute, Aug. 2001  http://www3.cancer.gov/prevention/methylation/summary.html 

Google = about 60 Nov. 5, 2004; about 139 Oct. 11, 2005; about 239 Nov 14, 2006

imaging biomarkers: The term biomarker is often associated with the detection or measurement (in vitro) of expressed genes, proteins, or metabolites in biological fluids. To drug developers, however, biomarker can refer equally well to morphological, functional, or molecular measurements made in vivo using medical imaging equipment, such as: Computed tomography (CT) Magnetic resonance imaging (MRI) Positron emission tomography (PET) Ultrasound and Optical scanners Molecular Imaging in Drug R&D and Medical Practice: Techno9logies, Applications, Markets, Insight Pharma Reports, 2008 http://www.insightpharmareports.com/reports/2008/92_Molecular_Imaging/overview.asp

in vitro diagnostic biomarkers: The U. S. Food and Drug Administration (FDA) is interested in the new high throughput microarray technology. As part of its outreach/ leveraging activity, the Agency desires to interact with industry to provide information on how its regulatory process is administered, to better understand the new technology, and to provide the opportunity to establish dialogues with industry prior to any marketing submissions. The speaker will note opportunities to industry in the development of FDA's regulatory program for high throughput microarray technology in the area of in vitro diagnostics for proteomics, pharmacogenomics, etc. In Vitro Diagnostic Biomarkers Regulatory Challenges and Opportunities, Dr. Joseph Hackett, Associate Director, Division of Clinical Laboratory Devices, CDRH, FDA  Protein Biomarkers  Aug. 25- 26, 2003 Philadelphia PA

Google = about 17 Sept. 2, 2004; about 36 Oct. 11, 2005, about 45 Nov 14, 2006

inclusion biomarkers: A biomarker that predicts that a given treatment will produce a positive response.

Google = about 4 Sept. 2, 2004; about 7 Oct. 11, 2005, about 21, Nov 14, 2006

indirect biomarkers: Biomarkers are very useful tools when the metabolic fate of the compound or the etiology of a resultant disease is completely understood. They may contribute to confusion if it is not possible to distinguish between markers of exposure and markers of disease. Such is the case for biomarkers used in the assessment of diisocyanate exposure. Biomarkers for diisocyanate exposure result from both direct and indirect effects. Molecules such as hemoglobin, albumin, tubulin, glutathione, and laminin have been implicated as having been directly modified as a result of exposure to toluene diisocyanate (TDI). In addition, indirect biomarkers have included profiles of molecules such as antibodies, cytokines, cell accumulation or proliferation, and markers of oxidative stress. WE Brown, AL Burkert, Biomarkers of toluene diisocyanate exposure Appl Occup Environ Hyg. 17(12): 840-845, Dec. 2002

Google = 148 about  Oct. 21, 2005, 295 Nov 14, 2006

kinetics of biomarkers: Comprises "formation, distribution, metabolism and excretion". However, this is at present neither an established science nor common practice in nutrition research on functional foods. As a consequence, sampling times and matrices, for example, are chosen on the basis of historical practice and convenience (for volunteers and scientists) but not on the basis of in depth insight. H Verhagen et. al, Assessment of the efficacy of functional food ingredients - introducing the concept "kinetics of biomarkers" Mutation Research 551(1-2): 65- 78, July 13, 2004 

Related term: Molecular Medicine glossary functional foods

known valid biomarker:  A biomarker that is measured in an analytical test system with well established performance characteristics and for which there is widespread agreement in the medical or scientific community about the physiologic, toxicologic, pharmacologic, or clinical significance of the results. Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations.  http://www.fda.gov/cber/gdlns/pharmdtasub.pdf 

marker gene: Are central to the research and development of transgenic plants. As scientists work to create plants that exhibit a desired new trait—for example, improved disease resistance—they insert a marker gene into the plant, along with the gene for the new trait. The marker gene clearly flags for researchers the cells that have the new trait (the transformed cells) so that they can quickly find, from among hundreds of young plants, those that have the desired characteristic. Canadian Food Inspection Agency,  Selectable Marker Genes in Transgenic Plants, 2004 http://www.inspection.gc.ca/english/sci/biotech/trans/marmare.shtml 

Google = about 8,670 Aug. 6, 2002; about 19,400 Aug. 18, 2003; about 30,200 Sept. 2, 2004, about 571,000 Nov 14, 2006

marker vaccines: Vaccines used in conjunction with diagnostic tests to differentiate vaccinated animals from carrier animals. Marker vaccines can be either a subunit or a gene-deleted vaccine. MeSH, 2001

markers: SNPs & Genetic Variations glossary

Types of genetic maps are differentiated largely by the type of marker used.

Google  markers biotechnology = about 52,100 Aug. 6, 2002; about 112,000 Aug. 18, 2003 about 171,000 Sept. 2, 2004
markers pharmaceutical = about 129,000 Sept. 2, 2004

Narrower terms: biological markers, biomarkers, DNA markers, ESTs, genetic markers, polymorphisms; SNPs & Genetic Variations glossary DNA fingerprints, microsatellite markers, microsatellite repeats, microsatellites,  minisatellite repeats, RFLPs, restriction enzymes, SSRs, STRs, STSs, satellites Related terms: Maps- genomic & genetic  

mechanism based biomarker: Biomarkers whose activity is mediated through the theoretical disease mechanism of action. Cambridge Healthtech Advisors, Biomarkers in Clinical Development: Implications for Personalized Medicine and Streamlining R&D report, 2005

metabolic biomarkers: At the non-clinical stage, metabolic biomarkers provide early profiles on drug efficacy, toxicity and mechanism, thus allowing more informed lead candidate selection. Many of these markers can be translated into the clinic, offering exploratory biomarkers of safety, efficacy, tolerability and pharmacodynamics. Metabolic biomarkers may also prove useful in advancing personalized medicine by allowing patient stratification and more effective clinical trial design. Metabolic biomarkers: Identifying and Validating Metabolic Markers for Drug Development September 17-19, 2007 • Philadelphia, PA

Google = about 143 Oct. 25, 2004, about 973 Nov 14, 2006; about 11,000 Apr 6, 2007

Related terms: Metabolic engineering glossary

metabolite biomarkers: Individual metabolites have already been used as disease biomarkers for years. ... Metabolomics enables the identification of biomarkers based on entire groupings of metabolites that are up- or downregulated in unison under specific conditions.  Charles W. Schmidt,  Metabolomics, What's happening downstream of DNA, Metabolite Biomarkers, Medscape, posted 6/1/2004   http://www.medscape.com/viewarticle/478878_3 

A single metabolite for which presence or expression level is significant.

Google = about 156 Oct. 25, 2004, about 126 Oct. 11, 2005, 352 Nov 14, 2006

metabolomic biomarkers: 

A pattern of metabolites that is able to discriminate or predict. 

Google = about 16 Oct. 25, 2004; about 304 Oct. 11, 2005, about 578 Nov 14,  2006; 

molecular biomarkers:  An early sign of change in an organism's physiological state - such as adaptation, stress or injury - due to environmental factors or disease.  Changes in molecules such as these [metallothionein] are sensitive and specific, making them useful sentinels of an organism's exposure to a specific environmental agent. Other molecular changes indicate progression of a disease process. The development of molecular biomarkers provides a link between ecologists or epidemiologists who study health effects in populations and molecular biologists who study the underlying mechanisms of these health effects. [Overview of the Molecular Biomarker Service at Dartmouth,  2001] http://www.dartmouth.edu/~cehs/Biomarkers/indexBM.html

Google = about 1,260 Aug. 6, 2002; about 2,040 Aug. 18, 2003; about 4,070 Sept. 2, 2004; about 35,000 Oct. 11, 2005, about 82,000 Nov 14, 2006

molecular diagnostics: Molecular Medicine & Diagnostics

molecular markers: The three most common types of markers used today are RFLP, RAPD and isozymes.  The classes of molecular markers, Mapping plant genomes with molecular markers, Phillip McClean, 1998  http://www.ndsu.nodak.edu/instruct/mcclean/plsc731/mapping/mapping1.htm 

Seems also to be an umbrella term for most of the terms in this glossary.

Google = about 31,100 Aug. 6, 2002; about 65,600 Aug. 18, 2003; about 122,000 Sept. 2, 2004, about 1,120,000 Nov 14, 2006

monitoring biomarkers: Reports reoccurrence or progression of disease.

Google = about 180 Sept. 2, 2004; about 213 Oct. 11, 2005, about 456 Nov 14, 2006

multiple biomarkers: A common statement -- A single biomarker will not be good enough to predict outcome, but combinations of biomarkers will be better at predicting outcome because each biomarker may represent a different aspect of the disease process.  Jeremy Taylor, Statistical Issues in Cancer Biomarker Assessment, Dept. of Biostatistics, Univ. of Michigan, 2004  http://mbi.osu.edu/2004/ws5materials/taylor.pdf 

Google = about 9,420 Oct. 11, 2005, about 23,500 Nov 14, 2006

multivariate markers:

Google = about 38 Sept. 2, 2004; about 58 Oct. 11, 2005, about 55 Nov 14, 2006

occurrence biomarkers: Reports an acute disorder.

Google = about 7 Oct. 25, 2004; about 9, Oct. 11, 2005

pharmacodynamic biomarkers: SEE Pharmacogenomics glossary 

Google = about 73 Oct. 25, 2004; about 148 Oct. 11, 2005, about 819 Nov 14, 2006

pharmacogenomics markers: the importance of pharmacogenomics markers has been demonstrated through the correlation of specific genetic variations in the CYP450 family

physiological biomarkers: Various physiological responses have been measured and utilized as biomarkers.  These include studies of such basic physiological functions as respiration, changes in growth rate, feeding, excretion, etc.  Physiological responses are used to provide integrated measures of an organisms well-being, based on a range of different functional attributes. An example of one such measure is growth.  Growth is an important fitness component of individual organisms, and may have an overall impact on the success of natural populations.  It is worth noting that although changes in a single fitness component may not always have a direct influence on the overall fitness of an individual, growth tends to integrate and reflect most sublethal effects. 

Google = about 799 Nov. 9, 2004; about 653 Oct. 11, 2005, about 11,000 Nov 14, 2006

PK/PD markers: Pharmacokinetic/pharmacodynamic markers

plasma biomarkers: SEE serum biomarkers

Google = about 250 Aug. 18, 2003; about 775 Sept. 2, 2004; about 11,600 Oct. 11, 2005, about 26,600 Nov 14, 2006

predictive biomarkers:  A biomarker that is present prior to an event occurring and which predicts that outcome.

Google = about 571 Sept. 2, 2004; about 839 Oct. 11, 2005, about 22,200 Nov 14, 2006

primary biomarkers:  

Google = about 65 Oct. 25, 2004, about 311 Oct. 11, 2005, about 177 Nov 14, 2006

Related term: secondary biomarkers

probable valid biomarker:  A biomarker that is measured in an analytical test system with well established performance characteristics, and for which there is a scientific framework or body of evidence that appears to elucidate the physiologic, toxicologic, pharmacologic, or clinical significance of the test results. A probable valid biomarker may not have reached the status of a known valid marker because, for example, of anyone of the following reasons: -- the data elucidating its significance may have been generated within a single company and may not be available for public scientific scrutiny., -- The data elucidating its significance, although highly suggest, may not be co conclusive. -- Independent verification of the results may not have occurred. Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations.  http://www.fda.gov/cber/gdlns/pharmdtasub.pdf 

prognostic biomarkers: See under biological markers

protein biomarkers: The challenge that the protein biomarker field is facing today is translation into clinical applications, partially due to the complexity of serum/plasma mixtures, the relative immaturity of proteomics technologies, and the high costs and low speeds of validation. New advances in mass spectrometry and other tools for biomarker discovery, focus on biomarker validation strategies,  examples of biomarker development for diagnostic and drug development applications will also be covered. Protein biomarkers: From Discovery to Validation September 17-19, 2007 • Philadelphia, PA.

Biomarkers can be protein or proteomic, but need not be. 

Google = about 386 Aug. 6, 2002; about 1,010 Aug. 18, 2003, about 3,750 Sept. 2, 2004, about 139,000 Nov 14, 2006

See also genomic biomarkers, metabolic biomarkers
Broader terms: biological markers, biomarkers
Related term: biosignatures

protein profiling: Expression glossary

protein variations: SNPs & other genetic variations

proteomic biomarkers: A protein expression pattern that is able to discriminate or predict. 

Google = about 26, Sept. 2, 2004; about 381 Oct. 11, 2005, about 820 Nov 14, 2006

regulatory biomarker: A biomarker being used to support scientific arguments made by the sponsor about drug dosing, safety, patient selection, or effectiveness, or that the sponsor proposes to describe in the drug label; or that are essential to achieve the dosing, safety, or effectiveness described in the drug label, or that will be used for decision making in any clinical trial or in an animal trial used to support safety. Cambridge Healthtech Advisors, Biomarkers in Clinical Development: Implications for Personalized Medicine and Streamlining R&D report, 2005

reporter biomarkers: A biomarker that is present as a result of an event occurring.

Google = about 4 Oct. 25, 2004; about 8 Oct. 11, 2005, about 6 Nov 14, 2006

response biomarkers: include measures of endogenous substances or parameters indicative of pathological or biochemical changes both toxicodynamic and pharmacodynamic, resulting from exposure to drugs and other chemicals. Biomarkers, Taylor & Francis, Aims & Scope http://www.tandf.co.uk/journals/titles/1354750x.asp  

response variability in biomarkers:  Biomarkers can be inappropriately applied or misinterpreted, because the fundamental assumptions in exposure– response relations have not been considered. Factors causing temporal and spatial variability in biomarker responses are reviewed. These include numerous geochemical and biotic variables. The variation can be minimised by appropriate study site selection, experimental replication, multivariate epidemiological approaches, normalised controls, and temporal calibration of responses; so that the regulatory use of biomarkers for biomonitoring and tracking pollution events, including chronic or multiple exposures to complex mixtures is possible. RD Handy et. al, A proposal for the use of biomarkers for the assessment of chronic pollution and in regulatory toxicology, Ecotoxicology, 12 (1-4): 331-343 Feb. 2003

safety biomarkers: Could be defined as the absence of any toxicity biomarkers. Safety/Toxicity Biomarkers, Toxicogenomics/ Toxicoproteomics to Assess Drug Safety and Reduce Attrition, Nov.  15-16, 2004, Philadelphia PA

Probably do not exist, since this could be defined as the absence of any toxicity biomarkers.

Google = about 194 Sept. 2, 2004; about 262 Oct. 11, 2005, about 605 Nov 14, 2006

secondary biomarkers: 

Google = about 22, Oct. 25, 2004; about 68 Oct. 11, 2005, about 113 Nov. 14, 2006

Related term: primary biomarkers

serum biomarkers: Physicians have used changes in serum biomarkers to judge response to therapy or to define the rate of disease progression. Many markers that are of limited value in screening for cancer are valuable for monitoring for recurrences. Distilling Cancer Biomarkers From the Serum Peptidome: High Technology Reading of Tea Leaves or an Insight to Clinical Systems Biology? Richard J. Robbins, Josep Villanueva, Paul Tempst, Journal of Clinical Oncology, 23(22): 4835- 4837, Aug. 1, 2005 http://www.jco.org/cgi/content/full/23/22/4835

Google = about 613 Aug. 18, 2003; about 701 Aug. 18, 2003; about 1,720 Sept. 2, 2004; about 19,100 Oct. 11, 2005, about 44,9000 Nov 14, 2006

Related terms: artificial intelligence based bioinformatics

SNP biomarkers: 

staging biomarkers: Distinguishes between different stages of a chronic disorder. 

Google = about 6, Oct. 25, 2004; about 21 Oct. 11, 2005, about 27 Nov 14, 2006

standard operating procedures SOPs:  In all pharmaceutical companies, standard operating procedures (SOPs) for planning, implementing, and employing biomarkers remain a work in progress, continually evolving as still-scarce outcomes data from biomarker-driven programs becomes available. Biomarker SOPs: Getting Optimum Value from Your Biomarker Programs report  January 2007 

surrogate biomarkers: A biomarker that reflects an indirect consequence of an event or disorder. Alternatively, secondary biomarker

Google = about 671 Sept. 2, 2004, about 932 Oct. 11, 2005, about 15,800 Nov 14, 2006

surrogate endpoint marker:  The rare biomarker that can substitute (or be a surrogate) for a clinical end point, such as survival, stroke, fracture, or cancer recurrence.  Stephen M. Hewitt^*, James Dear and Robert A. Star, Discovery of Protein Biomarkers for Renal Diseases, J Am Soc Nephrology 15:1677-1689, 2004  http://jasn.asnjournals.org/cgi/content/full/15/7/1677 

surrogate endpoints:  Outcome measures that are not of direct practical importance but are believed to reflect outcomes that are important. For example, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart attacks. Surrogate endpoints are often physiological or biochemical markers that can be relatively quickly and easily measured, and that are taken as being predictive of  important clinical outcomes. They are often used when observation of clinical outcomes requires long follow-up. Clarke M, Oxman AD, editors. Cochrane Reviewers Handbook 4.1.1 [updated December 2000]. In: The Cochrane Library, Issue 4, 2000. Oxford: Update Software. Updated quarterly  http://www.cochrane.dk/cochrane/handbook/hbookSurrogate_endpoints.htm

A biomarker intended to substitute for a clinical endpoint.  A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiology or other scientific evidence. Biomarkers Definition Working Group, 1998, Gregory Downing, NIH Initiatives in Surrogate Endpoints and Endpoint Analysis,  Nonclinical Studies Subcommittee, Advisory Committee for Pharmaceutical Science presentation, 2000  http://www.fda.gov/ohrms/dockets/ac/00/slides/3593S1_03_downing.ppt 

Google = about 2,570 Aug. 6, 2002; about 10,200 Aug. 18, 2003; about 9,200 Sept. 2, 2004; about 72,600 Oct. 11, 2005, about 128, 000 Nov 14, 2006

Related terms: biomarkers, surrogate markers.   

surrogate markers: A laboratory measurement of biological activity within the body that indirectly indicates the effect of treatment on disease state. CD4 cell counts and viral load are examples of surrogate markers in HIV infection. [GMHC Treatment Issues AIDS Medical Glossary, 1995]  http://www.critpath.org/research/gmhgloss.htm

Google = about 5,920 Aug. 6, 2002; about 22,300 Sept. 2, 2004; about 185,000 Oct. 11, 2005, about 370,000 Nov 14, 2006

Related terms: biomarkers, surrogate endpoints

susceptibility biomarkers:: include genetic factors which alter susceptibility to drugs and other chemicals.
Biomarkers, Taylor & Francis, Aims & Scope http://www.tandf.co.uk/journals/titles/1354750x.asp  

target biomarkers: A biomarker that reflects the presence of a specific molecular drug target.

Google = about 44 Sept. 2, 2004; about 154 Oct. 11, 2005, about 273 Nov 14, 2006

Related term: gene target: Targets glossary

toxicity biomarkers: The rising costs of drug development are putting pressure on pharmaceutical companies to reduce clinical attrition and maximize decision-making at the preclinical stage. One of the keys to reducing the cost and time of drug development is early and accurate safety evaluation of candidate drugs. The growing understanding of the toxicity mechanisms is creating an opportunity to develop toxicity biomarkers at the preclinical, clinical, and post-market stages. .  Toxicity Biomarkers: Optimizing Early Safety Assessment to reduce attrition, Sept. 17-19, 2007, Philadelphia PA  

Google about 407 Oct. 25, 2004; about 613 Oct. 11, 2005, about 714 Nov 14, 2006; about 9,290 April 6, 2007

Google = "toxicity markers" about  205 Aug. 6, 2002; about 186 Aug. 18, 2003; about 294 Sept 2, 2004, about 590 Nov 14, 2006,l about 757 Apr 6, 2007

toxicogenomics: Drug safety & pharmacovigilance glossary

translational research: Research glossary

tumor markers: Cancer genomics glossary

Related term: biological tumor markers

Google = about 19,000 Aug. 6, 2002; about 27,700 Aug. 18, 2003; about 66,500 Sept 2, 2004   "tumour markers" about 16,300 Sept. 2, 2004

type 0 biomarkers: Markers of the natural history of a disease and correlate longitudinally with known clinical indices, such as symptoms over the full range of disease states.... Type 0 markers can be characterized in phase 0 clinical studies, in which a reliable assay is used in a well defined patient population for a specified period of time. Ideally, a linear (positive or negative) relationship is established with the 'gold standard' clinical assessor.  Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003

Related term: Drug approvals glossary phase zero 

type I biomarkers: Capture the effects of an intervention in accordance with the mechanism of action of a drug , even though the mechanism may not be associated with clinical outcome. ...A priori validation of Type I biomarkers is impossible for truly novel targets without an effective positive control treatment. By definition, the more innovative the target, the less validated will be the associated biomarkers.  Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003

type II biomarkers: Are considered surrogate endpoints because a change in that marker predicts clinical benefit. ... Type II biomarkers (or surrogate end-points) must be relevant both to the mechanism of action of the drug and to the pathophysiology of the disease. Changes in the biomarker should reflect treatment benefit and therefore effective therapy is necessary for this validation. Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003

valid biomarker: A  biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic, or clinical significance of test results. The classification of biomarkers is context specific. Likewise, validation of a biomarker is context-specific and the criteria for validation will vary with the intended use of the biomarker.  The clinical utility (e.g. predict toxicity, effectiveness or dosing) and use of epidemiology/ population data (e.g. strength of genotype- phenotype associations) are examples of approaches that can be used to determine the specific context the necessary criteria for validation.  Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations.  http://www.fda.gov/cber/gdlns/pharmdtasub.pdf 

Narrower terms: known valid biomarker, probable valid biomarker

validation - biomarkers:  Cancer genomics glossary Cancer biomarker validation distinguishes between analytical validation and clinical validation. 

variants: SNPs & other genetic variations

Bibliography
Cambridge Healthtech Advisors, Biomarkers in Clinical Development: Implications for Personalized Medicine and Streamlining R&D report, 2005
Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework, Clinical Pharmacology and Therapeutics 69: 89- 95, 2001 http://ospp.od.nih.gov/biomarkers/ClinicalParmacology.pdf
Considerations in the evaluation of surrogate endpoints in clinical trials: Summary of a National Institutes of Health workshop, Controlled Clinical Trials 22¨485-502, 2001 http://ospp.od.nih.gov/biomarkers/cct.pdf
Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003
Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations.  http://www.fda.gov/cber/gdlns/pharmdtasub.pdf 
Insight Pharma, Disease Related Biomarkers: Their Potential in Patient Screening, Prognosis and Stratification, 2007 http://www.insightpharmareports.com/reports/2007/83_Disease_Biomarkers/overview.asp 
NIH Publications on biomarkers http://ospp.od.nih.gov/biomarkers/  Office of Science Policy & Planning

Alpha glossary index

How to look for other unfamiliar  terms

IUPAC definitions are reprinted with the permission of the International Union of Pure and Applied Chemistry.