Drugs must undergo rigorous testing before being approved by the Food and Drug Administration for use in humans. The initial testing is done with animals to determine the toxicity of the drug. Acute toxicity is the dose that is lethal or kills 50% of the laboratory animals tested. The testing is also done to determine what symptoms are experienced by the animals and the time the symptoms appear.
Sub chronic toxicity studies, conducted in at least two animal species, usually consist of daily administration of the drug for up to 90 days. Physical examinations and laboratory tests are performed throughout the study and at the end of the study to see what organs may have been adversely affected by the drug.
Chronic toxicity studies, also conducted in at least two species, usually last the lifetime of the animal but the length of the study may depend on the intended duration of drug administration to humans. Three dose levels are used, varying from a nontoxic low-level dose to a dose that is higher than the expected therapeutic dose and is toxic when given over a long period of time. Physical examination sand laboratory tests are performed to determine which organs are affected and whether the drug has the potential to cause cancer (carcinogenic).
Animal studies enable scientists to develop a therapeutic index for the drug. A therapeutic index is the ratio between the median lethal dose and the median effective dose. It tells a practitioner the safe dose to give for the therapeutic effect to be achieved.
Some drugs have a narrow margin of safety and require that the blood plasma levels be frequently monitored to assure that the drug stays within the therapeutic range. Drugs that have a wide margin of safety don’t require that the plasma levels be monitored. Digitalis (digoxin) is an example of a drug that has a narrow margin of safety and requires frequent monitoring of plasma levels.
Scientists also learn how the drug is absorbed, distributed, metabolized, and excreted once it is administered to the animals. This helps scientists predict how the drug will react when administered to humans.
Tests are also conducted in laboratory test tubes that can determine the Metabolism of the drug in humans, which may be different from animals. These are called in vitro studies. Once animal studies are successfully completed, the drug is ready for human trials during which human subjects are given the drug. There are three phases of human trial.
PHASE I: INITIAL PHARMACOLOGICAL EVALUATION
In Phase I, drug trials, the drug is given to a small number of healthy volunteers to determine safe dosage levels. The purpose is to document the dose level at which signs of toxicity first appear in humans, determine a safe tolerated dose, and determine the pharmacokinetics of the drug. Pharmacokinetics will be discussed in Chapter(Drug Action and Drug Interactions). Volunteers who give consent to participate are monitored closely during this phase. Permission must be obtained from the FDA to conduct Phase I clinical trials.
PHASE II: LIMITED CONTROLLED EVALUATION
The purpose of Phase II evaluation is to monitor drug effectiveness and any side effects. Individuals with the targeted disease participate in this phase of drug trials.
For example, antihypertensive (blood pressure lowering) drugs will be administered to patients who have hypertension (high blood pressure) to determine the drug’s effectiveness or optimal dose response range and for side effects. The number of participants is larger than Phase I trials but usually does not exceed 100 persons and every effort is made to use only people who have no other disorders or diseases.
PHASE III: EXTENDED CLINICAL EVALUATION
Phase III drug trials include many physicians and large groups of participants. When enough information has been collected to justify continued use of the drug, a New Drug Application (NDA) is submitted to the FDA. Usually, more than 4 years has passed between the drug’s selection and the filing of the NDA.
Phase IV studies are also called post-marketing follow-up. They are voluntarily conducted by pharmaceutical companies. These studies continue after the FDA has approved the drug and often include populations such as pregnant women, children, and the elderly. Manufacturers can find low-level side effects or can find that a drug is toxic and must be removed from market. The FDA continues to monitor new drugs even after they are marketed.
Drugs also undergo tests to determine the possible effects on a fetus. As a result of these tests, drugs are classified using the following Pregnancy Categories.
Adequate and well-controlled studies indicate no risk to the fetus in the first trimester of pregnancy or later.
Animal reproduction studies indicate no risk to the fetus, however there are no well-controlled studies in pregnant women.
Animal reproduction studies have reported adverse effects on the fetus, however there are no well-controlled studies in humans but potential benefits may indicate use of the drug in pregnant women despite potential risks.
Positive human fetal risk has been reported from investigational or marketing experience, or human studies. Considering potential benefit versus risk may, in selected cases, warrant the use of these drugs in pregnant women.
Fetal abnormalities reported and positive evidence of fetal risk in humans is available from animal and/or human studies. The risks involved clearly outweigh the potential benefits. These drugs should not be used in pregnant women.
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