Simon’s design is based on testing a null hypothesisH 0 :pap 0 , that the true
response ratepis less than some low and uninteresting levelp 0 , against an
alternative hypothesisHA:pbpA, that the true response ratepexceeds a cer-
tain desirable target levelpA, which, if true, would allow us to consider the
drug to have su‰cient antitumor activity to warrant further development. The
design parametersn 1 ,r 1 ,n 2 , andrare determined so as to minimize the num-
ber of patientsn¼n 1 þn 2 ifH 0 is true: The drug, in fact, has low antitumor
activity. The option that allows early termination of the trial satisfies high-
priority ethical concerns. The derivation is more advanved and there are no
closed-form formulas for the design parametersn 1 ,r 1 ,n 2 , andr. Beginning
users can look for help to Simon’s two-stage design, if appropriate.
12.7 PHASE II DESIGNS FOR SELECTION
Some randomized phase II trials do not fit the framework of tests of signifi-
cance. In preforming statistical tests or tests of significance, we have the option
to declare a trial not significant when data do not provide enough support for a
treatment di¤erence. In those cases we decide not to pursue the new treatment,
and we do not choose the new treatment because it does not prove any better
than the placebo e¤ect or that of a standard therapy. In some cancer areas we
may not have a standard therapy, or if we do, some subgroups of patients may
have failed using standard therapies. Suppose further that we have established
activity for a given drug from a previous one-arm nonrandomized trial, and the
only remaining question is scheduling: for example, daily versus one-every-
other-day schedules. Or we may wish to add another drug to that regimen to
improve it. In these cases we do not have the option to declare the trial not
significant because (1) one of the treatments or schedules has to be chosen
(because patients have to be treated), and (2) it is inconsequential to choose one
of the two treatments/schedules even if they equally e‰cacious. The aim of
these randomized trials is to choose thebettertreatment.
12.7.1 Continuous Endpoints
When the primary outcome of a trial is measured on a continuous scale, the
focus is on the mean. At the end of the study, we select the treatment or
schedule with thelargersample mean. But first we have to define what we
mean bybetter treatment. Suppose that treatment 2 is said to bebetterthan
treatment 1 if
m 2 m 1 bdwheredis the magnitude of the di¤erence betweenm 2 andm 1 that is deemed to
be important; the quantitydis often called theminimum clinical significant dif-
ference. Then we want to make therightselection by making sure that at the
PHASE II DESIGNS FOR SELECTION 457