n¼N=2 subjects. In this formula,pis the average proportion:
p¼p 1 þp 2
2It is obvious that the problem of planning sample size is more di‰cult, and a
good solution requires a deeper knowledge of the scientific problem: a good
idea of the magnitude of the proportionsp 1 andp 2 themselves. In many caes,
that may be impractical at this stage.
Example 12.5 Suppose that for a certain problem,d¼5 and it is estimated
thats^2 = 36. Then if we want to be 95% sure that the better treatment will be
the one with the larger sample mean, we would need
N¼ 4 ð 1 : 96 Þ^236
ð 5 Þ^2
F 24with 12 subjects in each of the two groups. It will be seen later that with similar
specifications, a phase III design would require a larger sample to detect a
treatment di¤erence ofd¼5 using a statistical test of significance.
12.8 TOXICITY MONITORING IN PHASE II TRIALS
In a clinical trial of a new treatment, severe side e¤ects may be a problem, and
the trial may have to be stopped if the incidence is too high. For example, bone
marrow transplantation is a complex procedure that exposes patients to a high
risk of a variety of complications, many of them fatal. Investigators are willing
to take these risks because they are in exchange for much higher risks asso-
ciated with the leukemia or other disease for which the patient is being treated;
for many of these patients, standard and safer treatments have failed. Inves-
tigators often have to face this problem of severe side e¤ects and contemplate
stopping phase II trials. Phase I trials focus on safety of a new investigational
medicine, and phase II trials are small trials to evaluate e‰cacy. However,
phase I trials are conducted with a small number of patients; therefore, safety is
still a major concern in a phase II trial. If either the accrual or the treatment
occurs over an extended period of time, we need to anticipate the need for a
decision to halt the trial if an excess of severe side e¤ects occurs.
The following monitoring rule was derived using a more advanced statis-
tical method called thesequential probability ratio test. Basically, patients are
enrolled, randomized if needed, and treated; and the trial proceeds continu-
ously until the number of patients with severe side e¤ects meets the criterion
judged as excessive and the trial is stopped. The primary parameter is the inci-
TOXICITY MONITORING IN PHASE II TRIALS 459