Statistical Methods in Medical Research 4ed

18.2 Phase I and Phase II trials 593
healthy subjects. The basic purpose in designing a Phase I trial is to estimate the
dose (the maximum tolerated dose (MTD)) corresponding to a maximum acceptable
level of toxicity. The latter may be defined as the proportion of subjects
showing some specific reaction, or as the mean level of a quantitative variable
such as white blood-cell count. The number of subjects is likely to be small,
perhaps in the range 10±50.
One approach to the design of the study is to start with a very low dose,
determined from animal experiments or from human studies with related drugs.
Doses, used on very small groups of subjects, are escalated until the target level
of toxicity is reached (Storer, 1989). This strategy is similar to the `up-and-down'
method for quantal bioassay (§20.4), but the rules for changing the dose must
ensure that the target level is rarely exceeded. This type of design clearly provides
only a rough estimate of the MTD, which may need modification when further
studies have been completed.
Another approach (O'Quigley et al., 1990) is the continual reassessment
method (CRM), whereby successive doses are applied to individual subjects,
and at each stage the MTD is estimated from a statistical model relating the
response to the dose. The procedure may start with an estimate based on prior
information, perhaps using Bayesian methods. Successive doses are chosen to be
close to the estimate of MTD from the previous observations, and will thus tend
to cluster around the true value (although again with random error). For a more
detailed review of the design and analysis of Phase I studies, see Storer (1998).
In a Phase II trial the emphasis is on efficacy, although safety will never be
completely ignored. A trial that incorporates some aspects of dose selection as
well as efficacy assessment may be called Phase I/II. Phase II trials are carried out
with patients suffering from the disease targeted by the drug. The aim is to see
whether the drug is sufficiently promising to warrant a large-scale Phase III trial.
In that sense it may be regarded as a screening procedure to select, from a
number of candidate drugs, those with the strongest claim to a Phase III trial.
Phase II trials need to be completed relatively quickly, and efficacy must be
assessed by a rapid response. In situations, as in cancer therapy, where patient
survival is at issue, it will be necessary to use a more rapidly available measure,
such as the extent of tumour shrinkage or the remission of symptoms; the use of
such surrogate measures is discussed further in §18.8.
Although nomenclature is not uniform, it is useful to distinguish between
Phases IIA and IIB (Simon & Thall, 1998). In a Phase IIA trial, the object is to
see whether the drug produces a minimally acceptable response, so that it can be
considered as a plausible candidate for further study. No comparisons with other
treatments are involved. The sample size is usually quite small, which unfortunately
means that error probabilities are rather large. The sample size may be
chosen to control the Type I and Type II errors (the probabilities of accepting an
ineffective drug and of rejecting a drug with an acceptable level of response). The