Drug Development: Non-Clinical Mutagenicity and Carcinogenicity Studies

The fundamental aim of non-clinical or pre-clinical studies in relation to new chemical entity (NCE) is to generate biological, pharmaceutical and toxicological data to ascertain that NCE would not cause any serious harm to the humans or would not cause cancer and/or genetic disorders through mutations. The limits of toxicological study of a NCE are decided with reference to route and duration of its intended use as a drug. Studies to evaluate carcinogenicity and mutagenicity of a NCE are performed in animals before it is declared as a drug and given to humans. Animal species usually used for carcinogenicity and mutagenicity are rats and mice, as some strains of these animals have very low incidence of spontaneous tumors and sufficient background knowledge about physiological parameters of these animals is available. Guidelines for such studies can be obtained from the regulatory agencies like FDA (USA), DCGI (India) and EMEA (Europe). The NCE is generally administered to the animals by at least two routes, one of which is usually the intended clinical route. The other route is usually intravenous so as to ensure adequate exposure of the animal to the new chemical entity. It is highly desirable to develop sensitive analytical methods for detecting the drug and its metabolites in the body fluids before starting the pre-clinical studies, as this would help in elucidating the toxicokinetics, pharmacokinetics, mutagenicity and carcinogenicity of the NCE. All studies need to be conducted in Good Laboratory Practice (GLP) compliance laboratories.

Carcinogenicity studies are needed to be done in adequate number of animals, depending on the regulatory requirements, before obtaining the approval for marketing of a drug. The drugs or compounds on which mutagenicity, carcinogenicity, teratogenicity and reproductive performance related effects need to be elucidated are of following types:

1. When the drug product is to be used for three months or longer period for at least six months - Carcinogenicity studies are must.
2. When the drug or compound is to be used frequently or in an intermittent manner in chronic or recurrent conditions like depression, anxiety and allergic rhinitis.
3. Prolonged exposure due to certain drug delivery systems makes it mandatory to carry out carcinogenicity studies.

Relaxations and Exemptions:

1. Genotoxic compounds are presumed to be trans-species carcinogens; hence long-term carcinogenicity studies are usually not needed.
2. Pharmaceuticals administered infrequently or for short duration of exposure (such as anesthetics and radiolabelled imaging agents) are exempted from carcinogenicity studies.
3. Carcinogenicity testing need not be conducted before market approval for the drugs developed for treating serious diseases.
4. If the life expectancy in the indicated population is short (less than 3 years), no long-term carcinogenicity studies are not required for the compounds to be administered to these subjects.

Drug Development: Non-Clinical Toxicity Study

Majority of allopathic drugs are developed from the organic or inorganic chemicals. The most important part of the process of drug development is the decision to take a new chemical entity (NCE) from a non-clinical to clinical phase. A lot of data needs to be generated through non-clinical safety study to evaluate the toxicity level of the NCE before it could be passed on for clinical phase of testing. The fundamental aim of non-clinical or pre-clinical studies is to generate biological, pharmaceutical and toxicological data to ascertain that NCE would not cause any serious harm to the humans. The limits of toxicological study of a NCE are decided with reference to the mode and duration of its use as a drug. Guidelines for such studies can be obtained from the regulatory agencies like FDA (USA), DCGI (India) and EMEA (Europe).

Why toxicity studies are necessary?

All chemical substances are poisons. Even the large doses of common salt (Sodium chloride) are poisonous and may affect our kidneys, heart and liver. Only a right dose differentiates a poison from a remedy. So, it is mandatory to conduct non-clinical or pre-clinical toxicity study for a NCE to generate pharmacological, toxicological and physicochemical data. There may be a dose which is safe and effective for humans otherwise a low dose would not generate any ill effect and a higher dose may produce deleterious effects. Non-clinical or pre-clinical toxicity studies of a NCE are performed in animals before it is declared as a drug and given to humans. Animal species usually used are mice, rats, guinea pigs, dogs and rabbits as lot of background knowledge about biological and physiological parameters of these animals is available.

Major goals of non-clinical toxicity studies:

1. Generation of data regarding dose response and physiological and biological toxic effects.
2. Identification of toxicities with respect to target organs if any.
3. Evaluation of time-dependence of effects or reversibility of toxic effects
   after discontinuation of NCE under study.
4. Identification of parameters required to be monitored effectively in human beings. Like liver function, renal function or thyroid function studies.
5. Evaluation of safe starting dose for the first-in human trial, and
6. Detection, identification and management of consequences of overdoses.