Pre and Post Approval Carcinogenicity Studies

Carcinogenicity studies are needed in adequate number and multiple species of animals before the marketing approval of a drug to evaluate trans-species carcinogenicity. However, for infrequently administered drugs or short duration exposure compounds like anesthetics and radiolabelled imaging agents, these studies are not mandatory. Post-approval carcinogenicity studies must be conducted for the pharmaceutical compounds developed to treat serious diseases. Endogenous peptides or their analogs or protein substances like animal insulin, pituitary-derived growth hormone and calcitonin, which are administered in very low doses, are exempt from pre or post approval carcinogenicity studies. Carcinogenicity studies should essentially be conducted for the analogs if:

• The dose to be administered is higher than the physiological dose.


• Significant variation in biological effects as compared to the natural counterpart.


• There is significant difference in the structure of synthetic compound as compared to natural counterpart.

Animals and doses for carcinogenicity studies:

The strains of animals selected for carcinogenicity studies should not have very high or very low incidence of spontaneous tumors. Rats are the most commonly used and accepted animals for such studies. However, the study may also be conducted on mice if the morbidity and rate of mortality of animals is not high during the period of study. Pre or post approval carcinogenicity studies should be conducted using at-least three dose levels. The highest dose should be sub-lethal and that should not reduce the life span of animals by more than 10% of expected normal life of animals. The lowest dose should be twice the intended therapeutic dose or same as therapeutic dose. The third dose should be intermediate dose between the highest and the lowest dose. An untreated group of animals as well as a vehicle control group should also be included in the study. There should be three groups of animals (50, 20 and 10 animals in each group) for high, intermediate and low dose of a drug. The period of dosing should be 24 months for rats and 18 months for mice. Equal number of animals of each sex should be included in each group of animals.The sacrificed and/or dead animals should be evaluated for neoplasia and histopathological changes in various organs and tissues. The effect on body weight, signs of intoxication and food intake should be recorded periodically. Urine analysis, hematology, biochemistry parameters, organ weights, gross pathology and detailed histopathology should be done for each animal under study. The description, site and dimensions of benign or malignant tumors developed should be recorded along with time of detection and histological typing should be worked out and recorded. Any benign or carcinogenic lesions detected during the post-approval carcinogenicity study should immediately be communicated to the Food and Drug Administration (FDA) or Drug Controller or Drug Research and Development Organization of you zone.

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.