Definition

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

• Pharmacodynamic biomarker: A response biomarker that indicates biologic activity of a medical product or environmental agent without necessarily drawing conclusions about efficacy or disease outcome or necessarily linking this activity to an established mechanism of action. Potential uses of a pharmacodynamic biomarker include establishing proof-of-concept, assisting in dose selection or measuring a response to medical products or environmental agents, including the use as a measure of potential harm. In some cases, such measures may be secondary endpoints in clinical trials and may be described in labeling.
• Surrogate endpoint biomarker: A response biomarker that is an endpoint used in clinical trials as a substitute for a direct measure of how a patient feels, functions, or survives. A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict that clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.

From a U.S. regulatory standpoint, surrogate endpoints and potential surrogate endpoints can be characterized by the level of clinical validation:

• validated surrogate endpoint
• reasonably likely surrogate endpoint
• candidate surrogate endpoint

Examples

The use of a biomarker as a pharmacodynamic biomarker or surrogate endpoint depends on its specific context of use, as demonstrated by the examples below:

Explanation

A response biomarker is used to show that a biological response, potentially beneficial or harmful, has occurred in an individual who has been exposed to a medical product or an environmental agent. A pharmacodynamic biomarker is a response biomarker that indicates biological activity of a medical product or environmental agent without necessarily drawing conclusions about efficacy or disease outcome or necessarily linking this activity to an established mechanism of action. 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. Pharmacodynamic biomarkers may be useful to establish proof-of-concept, i.e. that a medical product produces a pharmacologic response in humans. This information can be used to more specifically guide dose-response 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 B-lymphocyte targeted therapies required to maximally reduce this cell population, which is presumed to underlie the clinical benefits of these drugs in treating cancer. Pharmacodynamic biomarkers can provide evidence of target engagement; however, it may not always be possible to separate the direct biological effect of an agent from spontaneous changes in disease or medical condition.

An important use of response biomarkers is as Biomarkers of Potential Harm (BOPH), which measure effects consistent with harm due to exposure. These include early biological effects, alterations in morphology, structure, or function, and clinical symptoms (Stratton et al. 2001). An emerging application of BOPH is as response biomarkers for assessing potential health risks of new and novel tobacco products in the absence of long-term epidemiological evidence. A set of biomarkers, rather than a single biomarker, may be necessary to represent the multiple mechanisms by which tobacco causes diseases (Chang et al, 2019).

Response biomarkers that are intended to predict a clinical benefit in clinical trials may be considered as candidate, reasonably likely, or validated surrogate endpoints depending on the level of evidence.

Outside of medical product development, response biomarkers can also be used in clinical care settings. The main utility of response biomarkers in clinical practice is to guide dosing or continued use of a medical product. For example, the biomarker 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. Similarly, biomarkers of coagulation 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 warfarin doses can reduce the likelihood of bleeding complications and decrease the likelihood of stroke. In almost all cases in the clinical setting, response biomarkers are monitored because there is, or is thought to be, a link between the biomarker and clinical outcomes.

References

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