USE OF EXPERIMENTAL PHARMACOLOGY IN DRUG DISCOVERY AND DEVELOPMENT

The discovery and development of new drugs to provide medicines for treating diseases is the main role of the pharmaceutical industry. It is a challenging and expensive activity of pharmaceutical industry. Biological organisms and especially human beings are extraordinarily complex, and our understanding of how they function at the molecular level remains rudimentary, although considerable advances in knowledge have been made in recent decades. Whilst an advanced industrial society was able to plan and deliver a man to the moon following a 10-year program, almost 50 years on we are still only able to treat about 60% of cancer patients effectively, and do not understand how to correct most mental diseases. Development of new medicines is complex, time consuming and very expensive. The average cost of developing a new drug is estimated to be about US $ 1-1.2 billion, including expenditures on failed projects. This amount is about four times the price of an Airbus A380 at US $ 270 million, or five times that of a Boeing B - 787 Dreamliner at US $ 200 million.

Total drug development time grew from an average of 8.1 years in the 1960s to 11.6 years in the 1970s, to 14.2 in the 1980s, to 15.3 years for drugs approved from 1990 through 1995. Pharmaceutical companies and regulatory authorities are working together to reduce this time span. With the advent of technologies in biological screening procedures of new chemical entities the time involved in drug discovery has gone down in recent years but the cost of drug discovery has touched a new high. Success rate in getting from an initial compound to an approved and commercially available product is very low. Typically, tens of thousands of compounds are screened and tested, and only a handful makes it onto the market as drug products. The statistics are such that, out of the 10,000 compounds that show initial promise, only 0.3% will reach the testing stage for sub-acute study, five will go into human clinical trials, and only one will become an approved drug.

                    Table 1: Key stages of drug discovery and developments

Drug Discovery	Drug Developments
1.  Program selection (choosing a disease to                 work on)         2. Identification and validation a drug target         3.     Assay development         4.     Identification of a “lead compound”         5.     Lead optimization         6.     Identification of a drug candidate	1.     Preclinical study         2.     Clinical trials         3.     Release of the drug         4.     Follow-up monitoring

The process involves finding out the target that causes the disease. Next, chemical or biological compounds are screened and tested against these targets or assays, which are representative of these targets, to find leading drug candidates for further development. Many new scientific approaches are now used to determine targets (most targets are receptors or enzymes) and obtain the lead compounds; including the use of genomic technology, synthetic chemistry, recombinant DNA (rDNA) technology, laboratory automation and bioinformatics. Tests are performed on the lead compounds in test tubes (in vitro) and on animals (in vivo) to check how they affect the biological systems. The tests, often called preclinical research activities, include toxicology, pharmacodynamics and pharmacokinetics, as well as optimization of drug delivery systems. The leading compounds are modified and synthesized to improve their interactions with the targets, or to reduce the toxicity or improve pharmacokinetics performance. At the end of this process, an optimized compound is found and this becomes a potential drug ready for clinical trial in human. The development work has to follow Good Laboratory Practice (GLP) to ensure that proper quality system and ethical considerations are established. Only compounds that satisfy certain performance and safety criteria will proceed to the next stage of clinical trial. Then release of the drug occurs and follow up monitoring is required for confirming the effectiveness of the drug.           

Figure 1: Drug discovery and development processes.

After completion of preclinical studies successfully, the investigators files an ‘Investigational New Drug’ application (IND) to the government bodies such as Central Drugs Standard Control Organization (CDSCO), for allowance of initial testing in human beings. After the successful clinical trials and laboratory work, the investigators may file a New Drug Application (NDA). Permission to market a drug product will be given by the drug control authority after confirming the drug’s safety and effectiveness.