Glossary

Accelerated approval—regulatory mechanism by which new drugs meant to treat serious, life-threatening diseases or diseases for which there are no alternative treatments can be approved for marketing by the Food and Drug Administration (FDA) using earlier clinical trial results than would be required for regular approvals; postmarket surveillance and studies generally required

Analytical validation—“assessing [an] assay and its measurement performance characteristics, determining the range of conditions under which the assay will give reproducible and accurate data” (Wagner, 2002)

Angiotensin-converting enzyme (ACE) inhibitor—drug used to treat high blood pressure; prevents formation of a protein that causes constriction of blood vessels, thus lowering blood pressure

Apolipoprotein—a protein component of lipoprotein complexes

Assay—a biochemical or other measurement developed to quantitate a biomarker

Authorized health claim—voluntary statement that characterizes the relationship between a substance and its ability to reduce the risk of disease or a health-related condition (Schneeman, 2007) that meets the significant scientific agreement (SSA) standard

Beta-carotene ( β-carotene)pigment-producing molecule in the skin of several fruits and vegetables; after ingestion, some β-carotene in blood-stream converts to two molecules of retinol (preformed vitamin A)



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Glossary Accelerated approval—regulatory mechanism by which new drugs meant to treat serious, life-threatening diseases or diseases for which there are no alternative treatments can be approved for marketing by the Food and Drug Administration (FDA) using earlier clinical trial results than would be required for regular approvals; postmarket surveillance and studies generally required Analytical validation—“assessing [an] assay and its measurement per- formance characteristics, determining the range of conditions under which the assay will give reproducible and accurate data” (Wagner, 2002) Angiotensin-converting enzyme (ACE) inhibitor—drug used to treat high blood pressure; prevents formation of a protein that causes con - striction of blood vessels, thus lowering blood pressure Apolipoprotein—a protein component of lipoprotein complexes Assay—a biochemical or other measurement developed to quantitate a biomarker Authorized health claim—voluntary statement that characterizes the relationship between a substance and its ability to reduce the risk of disease or a health-related condition (Schneeman, 2007) that meets the significant scientific agreement (SSA) standard Beta-carotene (β-carotene)—pigment-producing molecule in the skin of several fruits and vegetables; after ingestion, some β-carotene in blood- stream converts to two molecules of retinol (preformed vitamin A) 10

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10 BIOMARKER AND SURROGATE ENDPOINT EVALUATION Biological plausibility—data elucidating how the biological pathways leading from exposure to effect are useful Biological products (biologics)—a category of products regulated by the FDA, including vaccines, blood and blood components, allergenic compounds, somatic cells, gene therapy, tissues, and recombinant ther- apeutic proteins Biomarker—“a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a[n] . . . intervention” (Biomarkers Defini- tions Working Group, 2001). Example: cholesterol level. The committee defines “objectively” to mean “reliably and accurately” Calcium channel blocker—drug used to treat heart failure caused by high blood pressure; effects the movement of calcium in the cells of the heart and blood vessels to relax blood vessels and increase the supply of blood and oxygen to the heart Cardiovascular disease—a term encompassing diseases that affect the heart and blood vessels CD4 cell (CD4+ T-cells)—specialized cells that play a role in measuring immune response in individuals with HIV Cholesterol—abundant steroid metabolite produced by animals and found in cell membranes and circulating in blood; excess cholesterol can lead to fatty deposits in blood vessels, a risk factor for cardiovas- cular disease Chronic disease—a culmination of a series of pathogenic processes in response to internal or external stimuli over time that results in a clini- cal diagnosis/ailment and health outcomes Clinical endpoint—a characteristic or variable that reflects how a patient [or consumer] feels, functions, or survives (Biomarkers Definitions Working Group, 2001) Clinical trial—a formal study carried out according to a prospectively defined protocol that is intended to discover or verify the safety and effectiveness of procedures or interventions in humans (IOM, 2007) Computed tomography (CT)—a special radiographic technique that uses a computer to assimilate multiple x-ray images into a two-dimensional, cross-sectional image, which also can be reconstructed into a three- dimensional image; can reveal many soft-tissue structures not shown by conventional radiography (IOM, 2007) Coronary heart disease (CHD)—refers to damage to the heart caused by atherosclerotic constriction of arteries supplying the heart; also known as coronary artery disease Correlation—a statistical association between two variables that does not imply a cause-and-effect relationship C-reactive protein (CRP)—an acute-phase, nonspecific, systemic bio- marker of inflammation; in normal individuals, CRP is a trace plasma

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10 GLOSSARY protein, but the serum concentration of CRP can increase upward of 1,000-fold upon exposure to a strong acute stimulus, such as sepsis or acute myocardial infarction Diagnosis—a conclusion as to the presence of a disease Diagnostic test—the investigative tools and techniques used in biologi- cal studies to identify or determine the presence of a disease or other condition. Any laboratory-based test that can be used in drug discov- ery and development as well as in patient care and clinical decision making (IOM, 2007) Dietary guidance statement—a statement describing general dietary pat- terns, practices, and recommendations that promote health; these make reference to categories of foods and not specific substances, and they do not describe relationships between a substance (specific food or food component) and a disease or health-related condition; these can be made without FDA review or authorization before use Drug—materials intended for use in the diagnosis, cure, mitigation, treat- ment, or prevention of disease; materials (other than food) intended to affect the structure or any function of the body of humans or other animals Efficacy—ability to produce a desired effect Epidemiologic studies—studies of the health of various human populations Food—articles used for food or drink for humans or other animals, chewing gum, and articles used for components of any such article; inclusive of foods consumed as part of meals and snacks, dietary supplements, and components contained in them (nutrients, other bioactive substances) Health claim—a claim that describes the relationship between a substance (food or food component) and a disease or health-related condition; limited to claims about disease risk reduction and cannot be claims about the cure, mitigation, treatment, or prevention of disease High-density lipoprotein cholesterol (HDL-C)—a lipoprotein of blood plasma that is composed of a high proportion of protein with little triglyceride and cholesterol and that is associated with decreased prob- ability of developing atherosclerosis Hypertension—abnormally high arterial blood pressure that is usually indicated by an adult systolic blood pressure of 140 mm Hg or greater or a diastolic blood pressure of 90 mm Hg or greater; can result in thick- ening and inelasticity of arterial walls and damage to the heart; a risk factor for various pathological conditions or events (e.g., heart attack, heart failure, stroke, end-stage renal disease, or retinal hemorrhage) In vitro diagnostic—a test that can detect disease, infection, or other health conditions

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110 BIOMARKER AND SURROGATE ENDPOINT EVALUATION In vivo—in the living body of a plant or animal Intervention—any drug, device, biologic, behavioral modification, nutri- tional modification, lifestyle modification, or other treatment intended to improve health Low-density lipoprotein cholesterol (LDL-C)—a lipoprotein of blood plasma that is composed of a moderate proportion of protein with little triglyceride and a high proportion of cholesterol and that is associated with increased probability of developing atherosclerosis Magnetic resonance imaging (MRI)—method by which images are cre- ated by recording signals generated from the excitation (the gain and loss of energy) of such elements as the hydrogen of water in tissue when placed in a powerful magnetic field and pulsed with radiofre- quencies (IOM, 2007) Medical device—any instrument, apparatus, appliance, material, or other article intended to be used to affect the structure or any function of a human or animal body Myocardial infarction—an acute episode of heart disease marked by the death or damage of heart muscle due to insufficient blood supply to the heart muscle, usually as a result of a coronary thrombosis or a coronary occlusion and that is characterized especially by chest pain Nutrient content claim—statements about the level of a nutrient or dietary substance in the product, using terms such as free, high, and low, or they compare the level of a nutrient in a food to that of another food, using terms such as more, reduced, and lite Pathophysiology—processes leading to the incidence or progression of disease or other health-related condition; alteration in function as dis- tinguished from structural defects Phase I trial—clinical trial in a small number of patients in which the toxicity and dosing of an intervention are assessed (IOM, 2007) Phase II trial—clinical trial in which the safety and preliminary efficacy of an intervention are assessed in patients (IOM, 2007) Phase III trial—large-scale clinical trial in which the safety and efficacy of an intervention are assessed in a large number of patients; FDA gener- ally requires new drugs to be tested in phase III trials before they can be put on the market (IOM, 2007) Positron emission tomography (PET)—a highly sensitive technique that uses radioactive probes to image in vivo tumors, receptors, enzymes, DNA replication, gene expression, antibodies, hormones, drugs, and other compounds and processes (IOM, 2007) Postmarket studies—may be mandated by the FDA for already approved drugs or devices to review potential risks Prentice criteria—stringent requirements to be met before a biomarker can definitively substitute for a clinical endpoint for a given use; briefly,

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111 GLOSSARY the criteria state that a biomarker must perfectly correlate with the clinical outcome it is meant to replace and capture the entire effect of the intervention used to bring about the effect on the clinical outcome Qualification—evidentiary process of linking a biomarker with biological processes and clinical endpoints Qualified health claim—voluntary statement that characterizes the rela- tionship between a substance and its ability to reduce the risk of dis- ease or a health-related condition (Schneeman, 2007) that does not meet the significant scientific agreement (SSA) standard Risk–benefit analysis—the comparison of the risk of a situation to its benefit Risk biomarker—a biomarker that indicates a risk factor for a disease Risk factors—variables that predict outcomes and are composed of bio- markers and social and environmental factors Significant scientific agreement (SSA)—judgment that qualified experts would likely agree that the scientific evidence supports the substance– disease relationship that is the subject of a proposed health claim Structure–function claim—statements describing the role of a nutrient or dietary ingredient intended to affect normal structure or function in humans; may characterize the means by which a nutrient or dietary ingredient acts to maintain such structure or function; may describe general well-being from consumption of a nutrient or dietary ingredi- ent; manufacturer is responsible for ensuring the accuracy and truth- fulness of the statement; FDA does not review these claims prior to manufacturer use Supplement—a product taken by mouth that contains a dietary ingredi- ent intended to supplement the diet; dietary ingredients may include: vitamins, minerals, herbs or other botanicals, amino acids, and sub- stances such as enzymes, organ tissues, glandulars, and metabolites; may be found in forms such as tablets, capsules, softgels, gelcaps, liquids, or powders Surrogate endpoint—a biomarker that is 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, pathophysiologic, or other scientific evidence (Biomarkers Definitions Working Group, 2001) Surveillance—population-level monitoring for early detection and treat- ment of advancing disease or complications Troponin—protein of muscle that together with tropomyosin forms a regulatory protein complex controlling the interaction of actin and myosin and that when combined with calcium ions permits muscular contraction (e.g., of the heart)

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112 BIOMARKER AND SURROGATE ENDPOINT EVALUATION Tumor size—inconsistently defined biomarker often used for determining efficacy of cancer therapeutics Type 2 diabetes—diabetes mellitus of a common form that develops especially in adults and most often in obese individuals and that is characterized by hyperglycemia resulting from impaired insulin utili- zation coupled with the body’s inability to compensate with increased insulin production utilization—contextual analysis based on the specific use proposed and the applicability of available evidence to this use. This includes a deter- mination of whether the validation and qualification conducted pro- vide sufficient support for the use proposed