Chapter: Modern Pharmacology with Clinical Applications: Progress in Therapeutics
Phases of Clinical Investigation
PHASES OF
CLINICAL INVESTIGATION
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.
Phase I
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 prac-tice 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 sin-gle dose of the test drug and closely observing the
sub-ject 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.
Phase II
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
evalu-ating 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.
Phase III
When an effective dose range
has been established and no serious adverse reactions have occurred, large
num-bers 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 sur-faced in the phase I and II trials, during which
exposure to the drug was limited. A new drug application is sub-mitted at the
end of phase III. However, for drugs in-tended to treat patients with
life-threatening or severely debilitating illnesses, especially when no
satisfactory therapy exists, the FDA has established procedures de-signed to
expedite development, evaluation, and mar-keting 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.
Phase IV
Controlled and uncontrolled
studies often are con-ducted 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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