In the broadest sense, a biomarker is an objective, measurable, and reproducible indicator of a patient’s medical signs. There are several more niche definitions of biomarkers: by EMA, by NCI, and by NIH, however perhaps the most universal definition is provided by WHO. The World Health Organization states that a true definition of a biomarker is “almost any measurement reflecting an interaction between a biological system and a potential hazard, which may be chemical, physical, or biological. The measured response may be functional and physiological, biochemical at the cellular level, or a molecular interaction”.
The term ‘biomarker’ was introduced in the 1950s, however it became widespread in the 1980s, when in the environmental studies it was proposed to establish a warning system of characterizing indicators to conduct checks on the state of wellbeing at a population level or with regards to an ecosystem, before pollutions of toxic substances occur. Priorly, the environmental research focused on identification of pollutants to prove environmental damages.
Biomarkers in Healthcare
Since the 1990s, the development of biomarker studies allowed biomarkers to be applied in healthcare, especially in the detection of diseases. Biochemical information can be gathered from blood, urine, and cerebrospinal fluids. As a result of biomarkers’ analysis, one can determine whether a factor represents a clinical manifestation, the stage in which the disorder is at, or even a surrogate manifestation.
Use in health risk assessment
Since the concept of active biomonitoring was developed in 1994, measurements that took place over a lengthy time span, are now employed in assessments of health hazards at work, but also in clinical settings, to evaluate the effect of drugs. These measurements as biomarkers ensure an important link between an exposure to a hazard, a dose of drug taken, and health impairment. Currently, biomarkers are important values in many health risk assessments.
Use for clinical diagnosis
In modern clinical settings, biomarkers may be used to confirm a diagnosis, to assess treatment, and to evaluate a prognosis in development of a disease. To reach desired results in these areas, a relationship between biomarkers and outcome hasto be identified and validated. In many cases, it may be beneficial to be able to compare the individual case with consecutive measurements over a period of time.
Use for health screening and monitoring
Biomarkers may be used to confirm the exposure of individuals to a particular substance, results may be juxtaposed or merged with results obtained per a geographic location, time period. Hence, biomarkers may facilitate the identification of dose-response relationships. Biomarkers are also used for screening. Population groups “at risk” may be found by deviations from mean values. WHO concludes that ‘in practice, ethical and social considerations, rather than cost, often preclude the widespread use of biomarkers for monitoring or surveillance purposes’.
Use in clinical trials
Biomarkers have a wide range of practical applications in clinical trials:
- Screening patients for eligibility to receive treatment
- Stratification of patients based on their symptoms
- Monitoring responses to treatment
- For reference studies to be used in future research
Various approaches are used for validation and application of different types of biomarkers (prognostic, predictive, etc.) in clinical trials. Clinical trials involving one or more (predictive) biomarkers may not be designed to validate them but rather to use them to optimize treatment selection (in biomarker-defined subgroups of patients).
Possible future uses
The areas of adoption mentioned above define the following outlook to possible employment of biomarkers in the future:
Research and stratification of patients may be based on combinations of targeted therapies based on biomarkers obtained from primary and metastatic tissue biopsies, other tissues, and imaging techniques. In addition to biomarkers used to select patients and monitor treatment efficacy and safety, biomarkers will be measured at baseline.
Designing clinical trials more efficiently may benefit the clinical decision-making process. Using more sensitive endpoints may assist in the registration of new drugs. Validating the early findings may continue to require large-scale random studies. It is expected that other clinical trial designs will be proposed and applied, and there are several types of clinical trial designs that incorporate biomarkers. Clinical trials have played an essential role in the development of new biomarkers and in bringing them from the laboratory to the clinic. In addition to serving key functions in trial operations, biomarkers are also essential to population selection and end point definition. As a result, biomarkers and clinical trials will remain inextricably linked. The implementation of biomarkers (including digital biomarkers) in clinical trials may change the way trials are planned and executed in the future.
Wider applications of biomarkers: they may expand from oncology to cardiology, neurology, psychiatry, and other areas.
Combinations of biomarkers may be employed wider in the future, to effect, for example, drugs development. Gene arrays may provide panels of relevant biomarkers in future pharmacogenomic approaches.
An increase in the use and popularity of connected digital devices and health-related mobile apps has created a new set of large, diverse, and complex data sets called “digital biomarkers.”
Wearables are improving health data gathering by understanding patient biometrics and functionality from fitness tracking, heart rate, heart rate variability, and sleep, to more disease-specific biometrics such as glucose monitoring, sweat analysis, electro-stimulation, and pressure sensors. Wearables have been used to support clinical trials across many therapeutic areas, including cardiovascular diseases, neurological disorders, respiratory disorders, sleep disorders, and pain. Study participants are tracked virtually outside the clinic as they go about their daily lives so that digitized trials can capture data on them.
Medical devices are beginning to be integrated into the digital realm, and digital biomarkers are emerging as an exciting new way to advance precision medicine and support clinical trials. It allows for personalized health baselines to be created based on individualized measurements.
While digital and traditional biomarkers address significant challenges related to the health-disease continuum in similar ways, there are also key differences in cultures, innovations, scientific and technical maturities, and the nature of the data. With regards to addressing health-related questions, digital biomarkers have the same advantages and disadvantages as traditional biomarkers, but they incorporate a digital and portable technology that adds a new dimension and presents a unique challenge.