Definition

A biomarker measured repeatedly for assessing status of a disease or medical condition or for evidence of exposure to (or effect of) a medical product or an environmental agent.

Examples

• Hepatitis C virus ribonucleic acid (HCV-RNA) level may be used as a monitoring biomarker when assessing treatment response in patients with chronic hepatitis C (AASLD and IDSA 2016, July; AASLD and IDSA 2016, September).
• International normalized ratio (INR) or prothrombin time (PT) may be used as monitoring biomarkers for assessing whether the desired effect of anticoagulation has been attained in patients on warfarin (Holbrook et al. 2012).
• Monoclonal protein (M protein) level in blood may be used as a monitoring biomarker to evaluate whether individuals diagnosed with monoclonal gammopathy of undetermined significance (MGUS) are showing signs of progressing to other disorders, including some types of blood cancer which may require treatment (Kyle et al. 2002).
• Prostate-specific antigen (PSA) may be used as a monitoring biomarker when assessing disease status or burden in patients with prostate cancer (Freedland and Moul 2007; Sandler and Eisenberger 2007; Thompson et al. 2007).
• Cancer antigen 125 (CA 125) may be used as a monitoring biomarker when assessing disease status or burden during and after treatment in patients with ovarian cancer (Gundogdu et al. 2011; Rustin et al. 2001).
• HIV-RNA may be used as a monitoring biomarker to measure and guide treatment with antiretroviral therapy (ART) (AIDSinfo 2007).
• B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) may be used as monitoring biomarkers during follow-up to supplement clinical decision making in pediatric patients with pulmonary hypertension (Kheyfets et al. 2015; ten Kate et al. 2015).
• Blood concentrations of an addictive drug may be used as monitoring biomarkers in drug addiction prevention and treatment trials to measure abstinence and compliance (ASAM 2001).
• Serial measurements of symphysis-fundal height during pregnancy can be used during antenatal screening to detect fetal growth disturbances (Papageorghiou et al. 2016).
• Urinary concentration of tobacco specific nitrosamines (TSNAs) (e.g., total N-Nitrosonornicotine (NNN) and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL) may be used as monitoring biomarkers for assessing exposure to tobacco and tobacco smoke (Yalcin and de la Monte 2016; Hecht 2002; IARC 2007; Hecht et al. 2008; Mallery et al. 2014; Park et al. 2015; Schick et al. 2017).

Explanation

A biomarker that is assessed repeatedly over time is called a monitoring biomarker and can be used to assess:

• Disease progression, including the occurrence of new disease effects, worsening of previously existing abnormalities, or change in disease severity or specific abnormalities
• Response of a disease or condition to a treatment, either favorable or unfavorable.

The scope includes biomarkers in a wide range of categories described in the BEST Resource (e.g., safety biomarkers, pharmacodynamic/response biomarkers, prognostic biomarkers). Biomarkers are usually assessed repeatedly when there is interest in not only the measured value of the biomarker, but also in the rate of change over time, the magnitude of change, the relation of changes to individual or patient (e.g., genotype or demographic), or disease-related characteristics (e.g., disease severity, disease duration, and specific disease).

In clinical care settings or in the context of a clinical trial, monitoring biomarkers may be measured during one or more periods of a patient’s clinical course – e.g., following diagnosis of a disease or condition and prior to intervention (e.g., to establish baseline characteristics, assess pre-treatment rate of progression), during the period in which an intervention is being delivered, or after delivery of the intervention has been completed. When assessed repeatedly, biomarker measurements may sometimes detect signs of disease or condition worsening, which may indicate deteriorating prognosis or a need for intervention. Biomarker monitoring during the course of an intervention can serve several purposes, including to determine how a drug is metabolized by a patient by monitoring drug concentration, to detect therapeutic effect or disease progression while on or following treatment, or to detect toxicity. Examples of these uses include measurement of PT and partial thromboplastin time (PTT) values to maintain warfarin or heparin levels within therapeutic range for patients undergoing anticoagulation treatment and monitoring of HCV-RNA levels to assess both the presence of hepatitis C infection that would benefit from treatment and evidence of response or non-response to treatment. Patients undergoing leflunomide and methotrexate therapy for rheumatoid arthritis are routinely assessed for evidence of liver toxicity by periodic measurement of liver enzymes. Serial imaging studies are used routinely for monitoring disease status in patients with solid tumors to detect regression or progression during or after therapy, or to detect recurrence after disease-free status is achieved with initial therapy.

Monitoring biomarkers are also used throughout medical product development, for example, in therapeutic or prevention trials of new drugs, biologics, or devices. Changes in biomarker measurements observed during or after treatment may provide supporting evidence of a pharmacodynamic effect or an early therapeutic response (see pharmacodynamic/response biomarker). A safety biomarker measured repeatedly in early phase clinical trials can be a type of monitoring biomarker for organ toxicity (see safety biomarker). Additionally, biomarkers are sometimes used in therapeutic or prevention trials to assess participant compliance with an assigned intervention. For example, the biomarker might be a blood level of the administered drug or it might be serum level of cotinine (an indicator of use of tobacco products) as part of an interventional trial that aims to prevent smoking. Thus, in addition to guiding clinical care, monitoring biomarkers may help to promote interpretability and credibility of interventional studies.

Monitoring biomarkers may be used for individual or population level surveillance for presence of diseases or medical conditions or risk of developing them. Monitored individuals may have no clinically apparent medical conditions or diseases, or they may have some medical condition or prior exposure that predisposes them to development of some new condition or disease. Healthy adults undergoing annual physical examinations are routinely monitored for levels of biomarkers such as serum cholesterol, blood glucose, and urine creatinine to evaluate risk for, and to detect emergence of, medical conditions such as hypercholesterolemia, diabetes, and impaired kidney function, respectively. The National Health and Nutrition Survey (NHANES)¹ conducts periodic examinations of individuals selected by a complex statistical sampling design from the U.S. population to learn about the health, including tobacco use, and diet of people in the United States. The Air Force Health Study (AFHS) was a congressionally mandated epidemiologic study designed to assess health effects of exposure to herbicides, particularly those with dioxin contaminants, used by Air Force personnel during the Vietnam conflict (Buffler et al. 2011). AFHS participants underwent periodic physical examinations to record clinical outcomes and serial collection of biospecimens, including blood, urine, semen, skin, fat, and stool samples, which could be analyzed for biomarkers of exposures (e.g., serum dioxin levels and epigenetic molecular markers of dioxin exposure) and indicators or risk factors for disease and other medical conditions (e.g., free immunoglobulin light chains in plasma cell disease, paraoxonase 1 (PON1) in type 2 diabetes and aging, sperm counts in reproductive health) (IOM 2015; National Academies of Sciences, Engineering, and Medicine 2016).

References

• AIDSinfo. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. December 1, 2007. Accessed October 2016. https://aidsinfo​.nih​.gov/guidelines/html​/1/adult-and-adolescent-arv-guidelines​/7​/hla-b--5701-screening.
• American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). When and in whom to initiate HCV therapy. July 2016. In: HCV guidance: recommendations for testing, managing, and treating hepatitis C. Accessed October 2016. http://www​.hcvguidelines​.org/full-report​/when-and-whom-initiate-hcv-therapy.
• American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). Monitoring patients who are starting hepatitis C treatment, are on treatment, or have completed therapy. September 2016. In: HCV guidance: recommendations for testing, managing, and treating hepatitis C. Accessed October 2016. http://www​.hcvguidelines​.org/full-report​/monitoring-patients-who-are-starting-hepatitis-c-treatment-are-treatment-or-have.
• American Society of Addiction Medicine (ASAM). Principles for Outcome Evaluation in the Treatment of Substance-Related Disorders: a Joint AMBHA-ASAM Statement. 2001. Accessed December 2016.http://www​.asam.org/docs​/default-source/public-policy-statements​/1outcome-evaluation-1-012​.pdf?sfvrsn=0.
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