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Importance of Clinical Trial for Drug Development

Scientists all over the world are in a continuous effort to develop new; drugs although drug development is an extremely arduous, highly technical and enormously expensive operation. Among the scientist, pharmacologists and chemists are more concerned with drug development who work jointly in evaluating new chemical entities (NCE) and gaining better understandings of active agents.

Until about one hundred years ago, most drugs used for the treatment of diseases were derived from naturally occurring substances of plant or animal origin, for example opium from the poppy, quinine from the cinchona tree and digitalis from the foxglove. In 1874 sodium salicylate was synthesized by Kolbe, introducing the era of synthetic therapeutics. Today the large majority of new therapeutic substances are synthesized in pharmaceutical laboratories and only few are obtained from natural sources.

The continuing accumulation of fundamental knowledge about disease and technological progress in molecular biology and biotechnology (such as the genetic manipulation of bacteria) has led to the development of much better animal and laboratory models for many diseases This makes the drug screening process more efficient and may also lead to decrease in the use of animals for research and pre-clinical development.

Synthesis and evaluation of thousands of NCEs are usually necessary for new drugs to be introduced in the market. Successful development must carry the cost of the failure. So, it is so much expensive which in U.S.A, is therefore ranged from 35 to 50 million dollar. Research and development of new drugs have been done under strict government regulations which have greatly increased over the past couple of decades.

Drug development comprises of two steps- preclinical development and clinical development:

Pre-clinical development:

Synthesis of new chemical entities is done as per research policy decision which is based on a) random synthesis of new compounds, b) structural variation of compounds with known pharmacological activity, c) biochemical and pharmacological insight and d) chance finding (serendipity).

The aim of the preclinical development phase for a potential new medicine is to explore the drug's efficacy and safety before it is administered to patients. In this preclinical phase, varying drug doses are tested on animals and/or in vitro systems (such as yeast and bacteria).

If active compounds are found, then studies on animal are done, studies in animal include pharmacodynamics, pharmacokinetics, toxicology (whether and how the drugs cause injury) and special toxicological (mutagenicity and definitive carcinogenicity) studies. In toxicological study, single dose is for acute toxicity and repeated doses are for sub-acute, intermediate and chronic toxicity. Full scale carcinogenicity study will only be required if the drug is to be given to man for more than one year. Most of the preclinical tests have to be conducted in accordance with the standards prescribed.

Clinical development:

About 1 in 1,000 NCEs reach this stage. At this stage, studies are along several lines. These lines are a) pharmaceutical study, b) pharmacological study, and c) studies in human or clinical trial.

Pharmaceutical study covers stability and formulation and compatibility of the NCEs with other tablet or infusion ingredients. Pharmacological study includes further chronic toxicological study in animal, initial animal metabolic and pharmacokinetic study. When studies in animals predict that a NCE may be a useful medicine i.e. effective and safe in relation to its benefits, then the time has come to put it to the test in man i.e. clinical trial.

Studies on human or clinical trial:

Clinical trial is a means by which the efficacy of drug is tested on human being. It may also give some idea about the risk involved, but usually this is not the primary consideration. Clinical trial is conventionally divided into four phases with each phase progressively testing the safety and efficacy of the compound.

Phase I (clinical pharmacology): This is the first exposure of the new drug on man which is usually conducted in healthy volunteers or patients which are designed to test the tolerability, dose, duration of action and other preliminary information of pharmacokinetic and pharmacodynamic aspects rather than efficacy. Trial of this phase is usually carried out in only one center on 20 to 50 subjects.

Phase II (clinical pharmacology): This phase comprises small scale trials on patients used to determine dose level and establish that the treatment offers some benefit. It usually involves 100 to 500 patients and is usually conducted in several centers.

Phase III (formal therapeutic trial): Full scale evaluation of treatment comparing it with standard treatment is done in this phase. It involves randomized control trials on 250 to 2,000 patients and is done in multiple centers.

Phase IV (post marketing surveillance): Information from all studies are received by the committee of safety of Medicines (CSM). If satisfied, product license is issued, and then the drug is marketed. Reports about the efficacy and toxicity are received from medical practitioners and reviewed by the committee of Review of Medicines. Renewal or cancellation of the product license depends on the comment of the Review committee.

The phases are arbitrary divisions of a continuous expanding process beginning with a single subject closely observed in the laboratory and proceeding to tens of volunteers through hundreds of patients to thousands before the drug is agreed to a medicine by a national regulatory authority and is licensed for general prescription. Studies in each phase should be adequately designed and controlled, but-the phases have on intrinsic merit.