Biomedical Engineering Reference
In-Depth Information
The clinical development of a new drug proceeds through three
key phases on the way to obtaining marketing approval (Fig.
1
).
A fourth phase of clinical testing (Phase IV) is usually conducted
after the drug is approved for marketing in order to obtain infor-
mation important for optimizing effective use of the drug. The
descriptions of the different phases of clinical trials are very similar
in both FDA and EMA documents [
10
,
11
] and are summarized
below.
2.3 Clinical
Development
A phase I study represents the first use of a new drug in human
subjects and is designed to evaluate the pharmacologic effects,
metabolism, and mechanism of action of the drug in humans,
as well as the tolerability of the dose range expected to be used in
later clinical studies. The goal is to generate sufficient information
to permit the design of well-controlled and scientifically valid phase
II studies (to investigate drug efficacy) [
10
,
11
].
Phase I studies usually do not have any therapeutic objectives
and are often conducted in healthy volunteer subjects rather than
patients, but they can be conducted in patients if deemed appropri-
ate. For example, the insertion of an intravitreal implant into an
otherwise healthy eye may not be considered appropriate; there-
fore, phase I studies of such treatments are generally conducted in
patients. When conducted in patients, phase I trials may provide
some preliminary insight into the efficacy of the new drug. The
total number of patients enrolled in phase I studies typically ranges
from 20 to 80 [
10
,
11
].
2.3.1
Phase I Studies
Phase II studies represent the first investigation of the therapeutic
efficacy of a new drug for a particular indication. They are well-
controlled trials conducted in patients with the disease or condition
for which the treatment is intended. These studies are usually
randomized and the investigators and/or patients are masked
with regard to study treatment, though this is not always appropri-
ate or feasible (as in the placement of an intraocular implant, for
example). The sample size is usually small (
2.3.2
Phase II Studies
200) [
10
,
11
], often
narrowly defined, and well-monitored throughout the study for
any safety signals. In addition to determining the potential efficacy
of the new drug, other important goals of phase II studies are to
determine the short-term adverse effects and risks associated with
the drug, as well as the most appropriate dose and dosing regimen
for phase III clinical trials [
10
,
11
].
Accurate dose-response information is important for under-
standing how the drug should be administered to maximize clinical
benefits while minimizing undesirable effects. Dose selection for
phase II and phase III trials is challenging for many drug devel-
opers, as a poor choice of dosing regimen may lead to trial failure.
Consequently, the use of several different doses or dose-escalation
protocols is common in phase II trials. The US FDA has a
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