Last few decades there have been revolution in the field of biomedical science that have enabled our healthcare professionals to diagnose, predict and characterize disease in ways no one would have ever imagined. A quite good lot of biomarkers were introduced which has enabled us to study about some of the most complicated mechanisms human body and mind. These biomarkers are providing vital information, enabling the physicians to make rational decisions in the diagnosis and therapeutics with impact of remarkable heights in patient healthcare. Biomarkers are playing very important role in diagnosis of a disease and provide précised assessment of diseased condition. It provides new hope to experimental medicine. It is an intermediate between treatment and disease. Biomarkers have always been beneficial in development of drugs and provide the most practical means of demonstrating its safety and efficacy. A novel branch of medical research ‘Translational Medicine' in which drug under trial is safe and effective in a disease target population has emerged.
Basically biomarkers refer to physiological indicator such as blood pressure, body temperature etc. that signalled on imbalance in body which provides direct evidential symptoms of disease. Now it is also used for detectable foreign substances such as radioactive isotopes whose passage through the system could indicate problems with specific organ or body function. US National Institute of Health Workers define biomarker as ”a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharma responses to a therapeutic interventions”. If the link between the biomarker and disease is established properly, it can be used to find out the diseased state with greater certainty, slightest change in diseased state can be observed with the help of biomarkers and vice versa. Every disease has various biochemical effect associated to it but every biochemical effect can not be used as biomarker for clinical practice. To be counted a biomarker it should have a peculiar characteristic that can be correlated to the diseased state of a patient. Biomarkers are broadly classified as biochemical, physiological, anatomic, histologic and physical (table1).
Table1. Biomarkers in clinical research and practice
| Type of biomarker | Examples |
| Biochemical | High sensitivity, c-reactive peptide, plasma b-type natriuetic peptide, plasma homocysteine,urinary albumin excretion, plasma renin activity. |
| Physiological | Blood pressure, pulmonary capillary wedge pressures,heart rate, pulmonary artery pressure, ventricular premature beats |
| Anatomic | Coronary vessel diameter (by coronary angiography), carotid intima media thickness(ultrasound), artheroscleroticplaque burden (intravascular ultrasound) |
| Histologic | Tissue biospy specimens |
| Physical | Skin colour, weight, height |
Alternatively biomarkers are also known as Natural history marker indicating them as biochemical indicator which is use to measure disease predisposition, its severity and out come. These are applied to describe an effective set of criteria for a patient who can be considered for undergoing clinical trials, or for stratifying patient populations. Eg: It includes genotypes for factor APOE is risk factor for Alzheimer’s disease. Markers that show effect a response to therapy or drug interaction are called as drug activity markers. They are used as proof to demonstrate, to established dose regimen and optimizing combination therapies. They are also used to measure pharmacodynamic response in which the magnitude of change defines the potency of the candidate drug.
Few examples of biomarkersi) HIV viral load is used as biomarker in development and assessment of highly active antiviral therapy (In 1980’s)
ii) Philadelphia chromosomes used as a biomarker to indicate which patients would benefit from drug candidates specially targeting the rogue protein (In 1960’s)
iii) HER-2 gene and receptor are used as biomarker or for breast cancer. (In 1980’s)
iv) Circulating tumour cells is used in oncology, present in the blood of cancer patients.
v) C-reactive protein (CRP) is used as inflammatory marker.
Biomarkers represent clinical end points whenever they are used directly to measures how a patient feels or functions. They are sometime also used to measure survival. In rare circumstances where a mark key may be a substituted for clinical end point, they are called surrogate end points. They are used to predict clinical benefit, or safety, based on epidemiological, therapeutic, or pharmacological evidence. The use of blood pressure (hypertension) as a surrogate for stroke. The B DWG discourages itself the term ‘surrogate marker’, as surrogate literally means ‘to substitute’ and surrogate therefore suggests substitution for a marker rather than for clinical end point. Liking a biomarker to us clinical end point involves establishing significant statical correlation with the disease process. Linkage is refers to validation which is also applied to performance characteristics of on assay or measurement such as sensitivity, specify and precision. Where as BDWG has recommended that the process of determine surrogate end point status to be referred as evaluation. Biomarker can be used for various purposes some of them are in listed below.
It is used to detect the predisposition of diseases in a population, screen for its presence, confirm its diagnosis, assess its severity and available to measure its clinical course. It can be used as target to discover new drugs providing improved systems for screening potential candidate and decreasing the number of false positive and false negative results. The availability of a viable biomarker is a very important factor in determining of continuation of research on an entity. Biomarkers shows it a particular drug leads to any side effect or not during clinical trials thus minimizes the risk of failure in forth phase of clinical trial. They also save huge amount of time and money during clinical trial by identifying suitable subjects for initial human testing. They provide reliable and also acquires less time. Biomarker helps in optimization of dose and measuring patient’s response more quickly and accurately.
They provide great deal of profit to the biomedical science still they are not used an o big scale it is potential off. Some daring innovators are trying to work with it because there is lack of interest shown by regulatory agencies. A range of biomarker is available which have potential to give reliable and accurate result but only few biomarkers are used as only they are under regulatory approval. Until phase 1 and phase 2 of clinical trial on pharmaceutical organization can use whatever biomarkers. It feels are most reliable as long as they are ethically acceptable but in phase 3 the organization is left with no choice but to use those biomarkers which will be accepted by regulatory agencies as evidence for approval. Some steps are taken by few of the regulatory agencies like FDA, Ministry of education, culture, sports science and technology and ministry of health, labour and welfare (Govt. of Japan) but they are not enough for requirement. Some major were taken by FDA to established a regulatory term and could expedite framework and could incorporation of biomarkers into the development process. Though the FDA has attempted to provide specific indication on the data that can be submitted but it only causes genomic biomarkers. By Government of Japan is actively promoting biomarkers research and proposed biomarker development as national project. Government has announced a programme related to investigation of Beta-42 Amiloid which has approach towards to Alzheimer’s disease and are trying to find out compound related to salivary amylase and peroxidation in fat as a biomarker for stress. Regulatory agencies should show some interest and give extra care for biomarkers. Innovates which are capable of working properly with help of biomarkers should work with it. Use of biomarkers at industrial level should will help the industry to be far ahead from its competitors and is economical. Biomarkers are indication of new era for biomedical science. Its just the first step, whole lot of possibilities are yet to be discovered.
The authors are with Manipal College of Pharmaceutical Sciences, Manipal, Karnataka 576104)