The clinical development of new drugs usually takes place in steps or phases conventionally described as clinical pharmacology (phase I), clinical investigation (phase II), clinical trials (phase III), and postmarketing studies (phase IV). Table 1.1 summarizes the four phases of clinical evaluation.
When a drug is administered to humans for the first time, the studies generally have been conducted in healthy men between 18 and 45 years of age; this practice is coming under increasing scrutiny and criticism. For certain types of drugs, such as antineoplastic agents, it is not appropriate to use healthy subjects because the risk of injury is too high. The purpose of phase I studies is to establish the dose level at which signs of toxicity first appear. The initial studies consist of administering a single dose of the test drug and closely observing the subject in a hospital or clinical pharmacology unit with emergency facilities. If no adverse reactions occur, the dose is increased progressively until a predetermined dose or serum level is reached or toxicity supervenes. Phase I studies are usually confined to a group of 20 to 80 subjects. If no untoward effects result from single doses, short-term multiple-dose studies are initiated.
If the results of phase I studies show that it is reasonably safe to continue, the new drug is administered to patients for the first time. Ideally, these individuals should have no medical problems other than the condition for which the new drug is intended. Efforts are concentrated on evaluating efficacy and on establishing an optimal dose range. Therefore, dose-response studies are a critical part of phase II studies. Monitoring subjects for adverse effects is also an integral part of phase II trials. The number of subjects in phase II studies is usually between 80 and 100.
When an effective dose range has been established and no serious adverse reactions have occurred, large numbers of subjects can be exposed to the drug. In phase III studies the number of subjects may range from several hundred to several thousand, depending on the drug. The purpose of phase III studies is to verify the efficacy of the drug and to detect effects that may not have surfaced in the phase I and II trials, during which exposure to the drug was limited. A new drug application is submitted at the end of phase III. However, for drugs intended to treat patients with life-threatening or severely debilitating illnesses, especially when no satisfactory therapy exists, the FDA has established procedures designed to expedite development, evaluation, and marketing of new therapies. In the majority of cases, the procedure applies to drugs being developed for the treatment of cancer and acquired immunodeficiency syndrome (AIDS). Under this procedure, drugs can be approved on the basis of phase II studies conducted in a limited number of patients.
Controlled and uncontrolled studies often are conducted after a drug is approved and marketed. Such studies are intended to broaden the experience with the drug and compare it with other drugs.
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