Principles and Practice of Pharmaceutical Medicine

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