PRECLINICAL AND CLINICAL EVALUATION OF TOXICITY

2005-04-09T06:47:00.000-07:00

This article has been published by the International Biopharmaceutical Association www.ibpassociation.org

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Before a drug is approved for general clinical use by the FDA, preclinical and clinical data showing substantial evidence of safety and efficacy are required by law. Drug studies proceed through various phases, as follows.
Preclinical Investigation (Animal Studies)
Animal studies used to determine or define the safety of a drug include studies of acute, subchronic, and chronic toxicity in several animal species.
The initial acute toxicity studies are to determine the median lethal dose (LD50), the toxic symptoms developed by the animals, and the time that they appear. At least 3 species of animals, one not a rodent, are usually used, and acute toxicity is usually determined by more than one route of administration.
Subchronic toxicity studies are conducted in at least 2 animal species and usually consist of daily administration of the test drug for up to 90 days. In each species, at least 3 dose levels are used, varying from the expected therapeutic doses to levels high enough to produce toxicity.
Chronic toxicity studies are carried out in at least 2 species, one of which is not a rodent. These studies usually last for up to the lifetime of the animal, but their length will depend on the intended duration of administration of the drug to humans.
Clinical Investigation (Human Studies)
Some adverse effects of drugs cannot be discerned in animals; e.g., dizziness, nausea, headaches, ringing in the ears, heartburn, and depression. It has been estimated that >= 50% of undesirable drug effects seen most frequently can be ascertained only during human trials.
Phase 1 represents the first administration of a new drug to man. A small number of closely monitored subjects, mainly healthy volunteers, are usually involved. Initially, each receives a single dose of the drug to determine a safe dose range and assess pharmacokinetic data. The primary objective of this necessarily cautious phase of the investigation is to determine a safe and tolerated dosage in humans; however, observation of toxicity, if it occurs, and of absorption, metabolism, and excretion may also be made during Phase 1.
Phase 2 begins after satisfactory preliminary evidence regarding safety has been obtained. It involves the supervised administration of the drug to patients for treatment of, or prophylaxis against, the disease or symptoms for which the drug is intended. These studies usually are conducted in randomized clinical trials comparing the new drug with the prototype drug, if any, for a particular indication. Often this is the first opportunity to observe the effect of long-term administration of the drug to humans.
Phase 3 begins after the initial phases have provided reasonable evidence of safety and efficacy. It consists of more widespread clinical trials that may move from the realm of clinical investigators to practicing physicians. Phase 3 extends up to the time the drug is released for general use.
Phase 4 is the study of the actual use of the drug in medical practice and, though often not recognized as a phase of clinical investigation, is a most important one from a clinical standpoint

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DRUG TOXICITY

PRECLINICAL AND CLINICAL EVALUATION OF TOXICITY