The development and testing process required to bring a new drug to market in the United States. Some requirements may be different for drugs used in life-threatening diseases.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 5-1.)

Animal Testing

The animal testing is required before human studies begin is a function of the proposed use and the urgency of the application. Thus, a drug proposed for occasional nonsystemic use requires less extensive testing than one destined for chronic systemic administration.

Because of the urgent need for new agents, anticancer drugs and drugs proposed for use in AIDS require less evidence of safety than do drugs used in treatment of less threatening diseases. Such drugs are often investigated and approved on an accelerated schedule.

Acute Toxicity

Acute toxicity studies are required for all new drugs. These studies involve administration of single doses of the agent up to the lethal level in at least 2 species (eg, 1 rodent and 1 nonrodent).

Subacute and Chronic Toxicity

Subacute and chronic toxicity testing are required for most agents, especially those intended for chronic use. Tests are usually conducted for a duration in proportion to the time proposed for human application, that is, 2-4 weeks (subacute) or 6-24 months (chronic), in at least 2 species.

Types of Animal Tests

Tests done with animals usually include general screening tests for pharmacologic effects, hepatic and renal function monitoring, blood and urine tests, gross and histopathologic examination of tissues, and tests of reproductive effects and carcinogenicity.

Pharmacologic Profile

The pharmacologic profile is a description of all the pharmacologic effects of a drug (eg, effects on cardiovascular function, gastrointestinal activity, respiration, renal function, and endocrine function, CNS). Both graded and quantal dose-response data are gathered.

Reproductive Toxicity

Reproductive toxicity testing involves the study of the fertility effects of the candidate drug and its teratogenic and mutagenic toxicity. The FDA uses a 5-level descriptive scale to summarize information regarding the safety of drugs in pregnancy (Table 5-1). Unfortunately, this scale is frequently out of date and not always accurate; it may soon be replaced. Teratogenesis can be defined as the induction of developmental defects in the somatic tissues of the fetus (eg, by exposure of the fetus to a chemical, infection, or radiation). Teratogenesis is studied by treating pregnant female animals of at least 2 species at selected times during early pregnancy when organogenesis is known to take place and by later examining the fetuses or neonates for abnormalities. Examples of drugs known to have teratogenic effects include thalidomide, isotretinoin, valproic acid, ethanol, glucocorticoids, warfarin, lithium, and androgens. Mutagenesis is induction of changes in the genetic material of animals of any age and therefore induction of heritable abnormalities. The Ames test, the standard in vitro test for mutagenicity, uses a special strain of salmonella bacteria that naturally depends on specific nutrients in the culture medium. Loss of this dependence as a result of exposure to the test drug signals a mutation. Many carcinogens (eg, aflatoxin, cancer chemotherapeutic drugs, and other agents that bind to DNA) have mutagenic effects and test positive in the Ames test. The dominant lethal test is an in vivo mutagenicity test carried out in mice. Male animals are exposed to the test substance before mating. Abnormalities in the results of subsequent mating (eg, loss of embryos, deformed fetuses) signal a mutation in the male’s germ cells.

TABLE 5-1 FDA ratings of drug safety in pregnancy.

Category Description A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote B Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters) C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only when the potential benefit justifies the potential risk to the fetus D

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