remembered that continuous responses can be con-
verted into quantal responses with appropriate,
prospective efficacy criteria. For example, blood
pressure is a continuous variable, but a drug may be
deemed effective or ineffective by stating prospec-
tively that a desired response is quantal positive
after a 15 mmHg fall in diastolic blood pressure
within 60 days of commencing therapy. Theoreti-
cally, this strategy can be implemented with groups
of patients treated in the same way instead of
individuals. Sometimes, this technique is termed
an ‘adaptive’ trial design, because dose size is
adapted according to the response of the previous
patient or group of patients.
The Armitage technique or ‘sequential analysis’
was originally employed in the testing of explosive
ordnance. Patients or groups of patients are paired
and then treated with alternative therapies. A con-
trol chart is developed that records the result of
each comparison with time, and crossing a bound-
ary on the chart after an unpredictable number of
paired comparisons gives the trial result. For a trial
of a new therapy that can both benefit and harm the
patient, a typical probability control chart forms a
‘double-triangle’ pattern, as shown in Figure 9.2.
The original methods have been extended in
many ways. The design of control charts is always
prospective, and their shape depends upon thea
prioriexpectations of the development team. For
example, when it is important to test only the
tolerability of a compound, the chart can have an
‘open top’: this is when it is important for the
Figure 9.1 The Dixon Up-Down (‘adaptive’) clinical trial design
Figure 9.2 The Armitage (‘sequential analysis’) clinical trial design
110 CH9 PHASE II AND PHASE III CLINICAL STUDIES