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FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Co-published by National Institutes of Health (US), Bethesda (MD).

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BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet].

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Pharmacodynamic/Response Biomarker

Published .

Definition

A biomarker used to show that a biological response has occurred in an individual who has been exposed to a medical product or an environmental agent.

Examples

Explanation

A pharmacodynamic/response biomarker is a biomarker whose level changes in response to an exposure to a medical product or an environmental agent. A change in a pharmacodynamic/response biomarker, such as a circulating small molecule (e.g., serum creatinine, blood sugar) or protein, or a physiologic measure, such as pupil diameter, ejection fraction, heart rate, or QT interval, provides early evidence that a treatment might have an effect on a clinical endpoint of interest or can be used to assess a pharmacologic endpoint related to safety concerns. It can also provide useful information for patient management, e.g., whether to continue treatment or to adjust dose, or for medical product development, e.g., did the drug have the pharmacodynamic effect thought to be related to clinical effect. Because of the serial nature of their assessment, pharmacodynamic/response biomarkers often fall under the category of monitoring biomarkers.

Pharmacodynamic/response biomarkers do not necessarily reflect the effect of an intervention on a future clinical event, i.e., they may not be accepted surrogate endpoints, but some are accepted in specific contexts: blood pressure, HbA1c, serum potassium, serum creatinine. Pharmacodynamic biomarkers can provide meaningful information about whether an intervention is biologically active, i.e., has the intended pharmacologic effect. Pharmacodynamic biomarkers are very important in the setting of early drug development trials, and can be used to measure the level of response to the intervention (as INR is for coumadin), and to guide clinical dose-response studies.

The main utility of pharmacodynamic/response biomarkers in clinical practice is to guide dosing or continued use of a drug or other intervention. For example, a biomarker like HbA1c is used to evaluate diabetes control following treatment with an antihyperglycemic agent. Such biomarkers may be used to gauge the level of response so that individual drug doses can be altered, or to identify whether therapies need to be added, subtracted or replaced. Pharmacodynamic/response biomarkers allow for more precise dose finding for therapeutic modalities. Biomarkers of coagulation, for example, are used to monitor warfarin therapy and adjust doses so that the biomarkers are kept within specific ranges. Because these biomarkers have been shown to correlate with clinical outcomes in atrial fibrillation, measuring coagulation parameters and adjusting doses can reduce the likelihood of bleeding complications and decrease the likelihood of stroke. In almost all cases in the clinical setting, pharmacodynamic/response biomarkers are monitored because there is, or is thought to be, a link between the biomarker and clinical outcomes.

In a medical product development setting, pharmacodynamic/response biomarkers may be useful to establish proof-of-concept that a drug produces a pharmacologic response in humans thought to be related to clinical benefit, and to guide dose-response studies. It is often very difficult to statistically power an early phase clinical trial to demonstrate a meaningful change in a clinical outcome, and many clinical outcomes require a long period of time before a meaningful change can be demonstrated. In these cases, pharmacodynamic/response biomarkers can provide evidence of target engagement. In addition, these biomarkers can be used in pharmacologic dose-ranging studies to determine which doses should be considered in trials that evaluate a clinical outcome. For example, B-lymphocyte suppression has been used to find doses of anti-CD20 monoclonal antibodies and other B-lymphocyte targeted therapies to determine what dose is required to maximally reduce this cell population, which is presumed to underlie the clinical benefits of these drugs in treating cancer.

References

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