Preclinical Research: An Important Aspect of Drug Development

Pharmaceutical medicine is “defined as the medical scientific discipline, concerned with the discovery, development, evaluation and registration of medicines. It is also concerned with the monitoring and medical aspects of marketing of medicines for the benefit of patients and public health”.

Pharmaceutical medicine is “defined as the medical scientific discipline, concerned with the discovery, development, evaluation and registration of medicines. It is also concerned with the monitoring and medical aspects of marketing of medicines for the benefit of patients and public health”.

Developing new medicines and making them available for patients is an international endeavor. Thus with the massive research and development efforts, the process of drug discovery has inevitably become subdivided into several functional divisions such as-

1. Basic chemical or structural research
2. Pre-clinical research and development
3. Clinical development
4. Regulatory and societal development
5. Post market approval medical affairs

Basic chemical or structural research: This involves exploring the genetic basis of a disease or the microstructure of a receptor or enzyme’s active site. It further involves developing tailored molecules to provide specific interactions and potential therapeutic outcomes.

Pre-clinical research and development: This involves exploring the causes of diseases and the potential safety and efficacy of new therapeutic agents, using biological systems including animal models.

Clinical development ( http://www.jli.edu.in ): For clinical development human subjects participant is must, both the healthy and those with a disease, to evaluate the safety and efficacy of a new drug/intervention.

Regulatory and societal development: Ensures that the entire development of each new therapeutic is seen in the context of its need to meet the governmental requirements. It also ensures that the appropriate value-added components such as quality of life, cost benefit ratio, evidence based medicine and relative aggressive positioning, over and above the essential term of safety and efficacy are integrated into the product’s database.

Post market approval medical affairs: It involves the promotion of each product by marketing and sales functions and the oversight of this process by pharmaceutical physicians.

Pre-clinical Research and Development

Preclinical studies require local toxicity studies such as acute, sub-acute, chronic toxicity studies and systemic toxicity studies such as genotoxicity and carcinogenicity studies. The information related with toxic effects is helpful for the estimation of an initial safe starting dose and dose range for the human trials and the identification of parameter for clinical monitoring for potential adverse effects.

Acute toxicity studies: Involve single-dose studies in animals are an important first step in establishing a safety profile, with the general aim of exploring a feasible dose range.

Repeated-dose toxicity studies: The studies are designed to identify safe levels of the drug following treatment regimens that are designed to provide continuous exposure of the animals to the test drug. Ideally, the route of administration should be the same as that planned in humans, whereas the animal studies should involve higher doses and longer durations of exposure than those planned clinically. Toxicokinetic data are also obtained from repeated-dose toxicity studies and generally determine the plasma concentrations of the drug and are generally collected on the first day of dosing and near the last day.

Subchronic/Chronic Toxicity Studies: The maximum duration of chronic studies is generally 6 months, although the ICH guidelines describe situations where studies of 9–12 month duration may be necessary in a non rodent species. The usual in life and postmortem observations are also performed.

Pharmacokinetic studies: In the early stages of drug development, it is important to identify important parameters that relate to the absorption and excretion pathways for the drug. In the later stages of development, studies on the extent of tissue distribution and the identification of metabolites become important. In some situations, where single-dose tissue distribution studies suggest drug localization, a tissue distribution study following repeated dosing may be indicated. The conditions under which such studies may be necessary have been delineated in an ICH guideline (Federal Register, 1 March 1997).

Reproductive toxicity: Studies for reproductive effects examine the possibility that agents may affect fertility of male or female, by specific pharmacological or biochemical means or by toxicity to a number of cell types, including gametes and their supporting cells. Some agents may alter the delicate hormone balance required for the mammalian reproductive process to maintain its cyclical progress.

Developmental toxicity: This concentrates on the most sensitive part of gestation, from the time of implantation until major organogenesis is complete. This is the period during which a test substance is most likely to cause malformation of the embryo.

Juvenile toxicity studies: Juvenile toxicity studies are recommended by both the Japanese and US regulatory agencies before inclusion of children in clinical trials. The studies are usually conducted in the offspring of untreated female rats by giving test material directly to the pups. Dosing usually does not commence until 4 days post partum, and is continued for 6 weeks.

Genotoxicity / Mutagenicity: These are in vivo or in vitro tests, conducted to detect compounds which induce genetic damage directly, or indirectly. These tests enable a hazard identification, with respect to damage to DNA, and its fixation.

Carcinogenicity studies: Carcinogenicity studies involve the treatment of rodents for long periods, approximating to the complete life span, in order to determine whether the test material assesses the capability to initiate or promote the development of tumors. Carcinogenicity studies have been required for all drugs where clinical therapy may extend for six months or longer.

Thus preclinical studies are helpful in discovering possible hazards to human beings who are exposed to much lower doses compared to administration of high animal doses, and the data obtained helps in assessment of the relevance of these findings to clinical safety, to support the choice of species and treatment regimen in non-clinical toxicity studies. Animal toxicity study data are required for clinical trials to be carried out and marketing of new drugs. Preclinical data is helpful in increasing the overall strategic success.

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