Definition And Classification Of Biomarkers

In 2001, the Biomarkers Definition Working Group, sponsored by the National Institutes of Health, defined a biomarker as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention"; a clinical endpoint as "a characteristic or variable that reflects how a patient feels or functions, or how long a patient survives" ; and a surrogate endpoint as "a biomarker that is intended to substitute for a clinical endpoint."

There are important differences among biomarkers. Type 0 biomarkers are natural history markers of a disease and tend to correlate longitudinally with known clinical references, such as symptoms. Type I biomarkers capture the effect of an intervention in accordance with the mechanism of action of the drug, even though the mechanism might not be known to be associated with the clinical outcome. Type II biomarkers are considered surrogate markers since the change of a specific marker predicts a clinical benefit (Frank and Hargreaves, 2003).

A hierarchy also exists among clinical endpoints. A clinical endpoint can be defined as an intermediate endpoint, which is a clinical endpoint that is not the ultimate outcome but is nonetheless of real clinical benefit; the ultimate outcome is a clinical endpoint such as survival, onset of serious morbidity, or symptomatic response that captures the benefits and risks of an intervention (Lesko and Atkinson, 2ooi).

Classification can be made according to the specificity of a biomarker versus the intended therapeutic response. A linked drug biomarker demonstrates a strict correlation between the pharmacological action of the drug and its effect on the disease. Danhof et al. (2oo5) have proposed to classify biomarkers in three distinct categories: (i) pharmacological and (2) toxicological markers, both observed in healthy subjects, and (3) pathological biomarkers observed in subjects affected by disease (Danhof et al., 2oo5). It is noteworthy to review the definition of biomarkers from the 2oo3 FDA "Guidance for Industry: Exposure-Response Relationships":

• Biomarkers are considered valid surrogates for clinical benefit (e.g., blood pressure, cholesterol, viral load).

• Biomarkers are thought to reflect the pathologic process and at least be candidate surrogates (e.g., brain appearance in Alzheimer's disease, brain infarct size, various radiographic/isotopic function tests).

• Biomarkers reflect drug action but of uncertain relation to a clinical outcome (e.g., inhibition of ADP-dependent platelet aggregation, ACE inhibition).

• Biomarkers may be more remote from the clinical benefit endpoint (e.g., degree of binding to a receptor or inhibition of an agonist).

Classification Based on Mechanism of Action

The COST B15 working group 2, "Markers of Pharmacological and Toxicological Action," has proposed a conceptually similar classification. Based on the location of the biomarker in the chain of events from underlying subject genotype or phenotype to clinical scales, the following types of biomarkers have been be defined:

Type 0: genotype or phenotype Type 1: concentration Type 2: target occupancy Type 3: target activation

Type 4: physiologic measures or laboratory tests Type 5: disease processes Type 6: clinical scales.

This classification is not universally accepted since the type 0 biomarker relating to a subject ' s genotype or phenotype can be considered a covariate rather than a biomarker. Similarly, the type 6 biomarker, such as a clinical scale, can be regarded as a measurement of a clinical endpoint and not a bio-marker. These classifications have been proposed in attempt to reconcile disagreements on the potential role of biomarkers.

Classification Based on Clinical Applications

The paradigm is now shifting from the classical model of clinical care to development and application of biomarkers in different therapeutic areas according to their clinical application, which can be classified as follows:

• Preventive biomarkers, which identify people at a high risk of developing disease

• Diagnostic biomarkers, which identify a disease at the earliest stage, before clinical symptoms occur

• Prognostic biomarkers. which stratify the risk of disease progression in patients undergoing specific therapy

• Predictive biomarkers. which identify patients who respond to specific therapeutic interventions

• Therapeutic biomarkers, which provide a quantifiable measure of response in patients who undergo treatment

Classification According to Measurement Scale

From a mathematical perspective, biomarkers can also be classified on the basis of the measurement scale it utilizes:

• Graded response, which is a quantifiable biomarker that is causally linked to drug treatment and temporally related to drug exposure (e.g., blood pressure, cholesterol). Usually such endpoints are chosen based on the pharmacodynamic response.

• Challenge response, which is a quantifiable graded response to a standardized exogenous challenge, modified by the administration of the drug (e.g., challenge test in asthma).

Usually, these markers are based on the mode of administration (MoA) of the drug and the response is a continuous variable. Other types of responses can be observed with biomarkers:

• Categorical response is usually a "Yes" or "No" response for a clinically relevant outcome based on the disease progression, regardless of MoA (e.g., response based on tumor size, incidence of an AE); such an event is generally not linked to the MoA of the drug.

• Time to event response is usually a clinically relevant outcome regardless of the MoA, such as survival time or time to relapse. It is a censored continuous clinical variable which can be measured only once for each patient.

• Event frequency/rate of response is the frequency of clinical events related to drug exposure (e.g., MRI lesions in multiple sclerosis); it is usually a censored continuous variable.

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