Assessment of the safety of drugs for animals.

In summary, the evaluation of the safety of drugs for animals should take advantage of the fact that toxicity can be evaluated in the target species. Acute studies are useful in providing information for dose setting and the possible relevant observations that can be incorporated in the protocol for a longer, more definitive study; however, they are of limited value in the final evaluation of a drug. Longer tests should be conducted to mimic the conditions of use as much as possible, using labeled and exaggerated doses. Flexible protocols should be individually designed for each study. Clinical studies, conducted in several locations at different times of the year if appropriate, should supplement the laboratory studies. New equipment and methodology facilitate measuring even more subtle toxic effects. It is easy to evaluate a compound that kills animals, that causes colic or other gastro-intestinal signs, or that results in serious neurological impairment, such as circling or blindness, shortly after treatment. But the line is blurred between subtle toxic effects and physiological change. When a rise in serum enzymes, an increase in smooth endoplasmic reticulum or a decrease in formed elements of the blood is demonstrated, the significance of the effects produced must be evaluated in the context of the clinical aspects of the proposed usage. A knowledge of medicine and/or drug action and interaction is necessary to make this appraisal. It is incumbent upon the sponsor to discuss thoroughly all aspects of the toxic effects detected, and it is incumbent upon the reviewer to understand them.