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.
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