Emerging Biomedical concepts

Zero-Phase Human Trials (Human First Approach)

Phase I, II, III and multi-centric human clinical trials following pre-clinical and animal toxicity data collection are the accepted norms for drug development. Industrial sources suggest that development of a new molecule of a drug requires an investment of one billion dollars and a development period of 10 to 15 years, while a new formulation (treated as a new drug by regulators) requires an investment of $ 600-800 million and an incubation period of 10 years. It also requires involvement of teams of experts belonging to different specialties (chemists, biochemists, analysts, pharmacologists, toxicologists, medical scientists, statisticians, IPR lawyers and regulators, etc) at different stages. As per global statistics, 80 to 85 per cent biomedical products fail before or during human trial stage, becoming a major cause of financial and man-years wastage. Only large industrial houses are therefore able to participate in the trillion dollar drug industry leading to monopoly and exorbitant pricing of newly marketed drugs. The recent biotechnology, nanotechnology and genomic revolutions have ensured that novel drug development would remain at the forefront of the global research and development.
The concept of zero-phase clinical trial has recently emerged as a potential long-term solution to this vexing socio-economic problem. It is based on the fact that pharmacological (and sometimes toxicological) effects of a novel drug can be detected and quantified using single dose of very small amount of the drug on human through non-invasive imaging technologies like nuclear medicine (including PET) and MRI in an ethical and safe way. These diagnostic modalities are sensitive enough to register the fine molecular, biochemical, metabolic or physiological perturbation caused by the drug. This is done ahead of the lengthy and costly drug development cycle. Any drug that fails to reveal the desired or expected pharmacological effect in human on non-invasive imaging (or shows likelihood of unexpected toxicity) is likely to fail during the detailed clinical studies and may be discARDEd at the initial stage only.
DRDO has a number of non-invasive imaging modalities that are used for routine clinical diagnostic purposes, and is acquiring state-of-the-art PET-CT-Cyclotron and 3-T MRI machines under the drug development programme. A beginning has been made in India by DRDO to use the `human firstí approach to evaluate its own novel drug formulations. After taking clearance from human ethical committee and employing all safety norms, a number of new formulations have been developed using this approach within a short span of time.



Estimating release rate of SBM ointment by radiometry

Pharmacoscintigraphy is the branch of nuclear medicine DEALing with development of novel drugs and delivery systems. It is now emerging as the preferred method of zero-phase clinical trial and DRDO has been responsible for developing it into a usable technology in India. Twenty-eight new or novel uses of the technology have been demonstrated so far by DRDO, classifiable into four modules: a) in vitro radiometry, b) radiolabelling of drugs followed by human use to get pharmacokinetic and pharmacodynamic information, c) radiolabelling of a drug or an excipient to follow its path in the human body, and d) diagnostic nuclear medicine to record pharmacological action of a drug. At least eight human models have been identified for quantitative evaluation of efficacy of different groups of drugs. More than 20 patents have been filed using this technology till now by DRDO.
An example each of the four scintigraphy modules developed by DRDO is presented below:



Radiolabelling of a drug (INH) for biodistribution studies

Module 1: Linear pattern of drug release from an ointment is confirmed using radioactivity.
Module 2: Radiolabelling of a drug (INH) for biodistribution studies in the human body. Parameters generated with radioactive drug were similar to that of the parent molecule.
Module 3: Examples of excipient labelling to characterise a tablet dissolution behaviour in human body. Slow-release, duodenal release, and colon-release systems.
Module 4: Creation of human models for drug development using conventional nuclear medicine is a new concept and is part of the zero-phase human trial initiative of DRDO.
Eight pharmacoscintigraphy models wherein efficacy of a new drug is tested in comparison to the conventional drug in the human being directly have been developed at DRDO. These include ischemia models, gastric acidity and motility models and antiinflammation/ antibacterial action models etc. This not only provides reproducible and objective evidence of the drug action without compromising the safety aspects, but also saves a significant amount of time and financial outlay. One such example is comparison of antiinflammatory activity of novel drugs compared to known ones like aspirin or brufen in knee osteoarthritis.

MRI & Nuclear Medicine Techniques for Cancer Detection

Tc-99m GHA brain scan

DRDO has perfected several MRI and nuclear medicine techniques for accurate diagnosis of cancer of the brain, particularly following surgery for cancer removal. Before these techniques, it was practically impossible to differentiate cancer recurrence from post-raDIATion fibrosis or necrosis. The MRI advancements in this direction include MR perfusion sequences, MR spectroscopy and MR choledocho-pancreography (ERCP), and MR angiography.
Apart from cancer detection, the technology has significant implications for non-invasive diagnosis of a number of organ specific diseases, as well as for drug development. Introduction of 3-Tesla MRI shall enhance this capability further, extending it to several other types of cancer. Nuclear medicine innovations giving similar results include delayed imaging protocol, SPECT-CT co-registration, and the conclusion that indigenous Tc-99m GHA gives similar results of cancer detection compared to the conventional cancer-imaging radiotracer Tc-99m MIBI that is imported and is ten times costlier. The critical target-to-background ratio has been identified, which gives the highest accuracy in differentiating benign from malignant brain lesions. A databank of more than 60 cases suggests that the accuracy of detection is more than 90 per cent.