The response rate is the proportion or percentage of patients who respond. A
phase II trial may be conducted in two stages (as will be seen in Section 12.6)
when investigators are concerned about severe side e¤ects. A second type of
phase II trial consists of small comparative trials where we want to establish the
e‰cacy of a new drug against a control or standard regimen. In these phase II
trials, with or without randomization, investigators often test their validity by
paying careful attention to inclusion and exclusion criteria.Inclusion criteria
focus on the definition of patient characteristics required for entry into a clini-
cal trial. These describe the population of patients that the drug is intended to
serve. There areexclusion criteriaas well, to keep out patients that the drug is
not intended to serve.
Phase III and IV trials are designed similarly. Phase III trials are conducted
before regulatory approval, and phase IV trials, which are often optional, are
conducted after regulatory approval. These are larger, controlled trials, whose
control is achieved by randomization. Patients enter the study sequentially and
upon enrollment, each patient is randomized to receive either the investiga-
tional drug or a placebo (or standard therapy). As medication, the placebo is
‘‘blank,’’ that is, without any active medicine. Placebo, whose size and shape
are similar to those of the drug, is used to control psychological and emotional
e¤ects (i.e., possible prejudices on the part of the patient and/or investigator).
Randomizationis a technique to ensure that the two groups, the one receiving
the real drug and the one receiving the placebo, are more comparable, more
similar with respect to known as well as unknown factors (so that the conclu-
sion is more valid). For example, the new patient is assigned to receive the drug
or the placebo by a process similar to that of flipping a coin. Trials in phases III
and IV are often conducted as adouble blind, that is, blind to the patient (he or
she does not know if a real drug is given so as to prevent psychological e¤ects;
of course, the patient’s consent is required) and blind to the investigator (so
as to prevent bias in measuring/evaluating outcomes). Some member of the
investigation team, often designated a priori, keeps the code (the list of which
patients received drug and which patients received placebo) which is broken
only at the time of study completion and data analysis. The termtriple blind
may be used in some trials to indicate the blinding of regulatory o‰cers.
A phase III or IV trial usually consists of two periods: an enrollment period,
when patients enter the study and are randomized, and a follow-up period. The
latter is very desirable if long-term outcome is needed. As an example, a study
may consist of three years of enrollment and two years of follow-up; no
patients are enrolled during the last two years. Figure 12.1 shows a description
of a typical phase III or IV clinical trial.
12.3 DESIGNING PHASE I CANCER TRIALS
Di¤erent from other phase I clinical trials, phase I clinical trials in cancer have
several main features. First, the e‰cacy of chemotherapy or any cancer treat-
448 STUDY DESIGNS