Principles and Practice of Pharmaceutical Medicine

very efficient in the use of subject resources. One
disadvantage of blocked designs is that they do not
allow for missing data. If data from one subject in
the block are missing, the entire block may be
disqualified.
A variation on the idea of blocking is thecross-
overdesign. Here, each block consists of one sub-
ject who receives the study treatments in a random
order. Crossover experiments are frequently used
in bioavailability and pharmacokinetic studies.
The reason is that the pharmacokinetic parameters
which determine the absorption, distribution,
metabolism of the drug in the body and its elimina-
tion form the body depend on the biological
makeup of the subject and vary, often considerably,
from subject to subject. Thus, the inter-subject
variability is typically much higher than the intra-
subject variability. In crossover studies, the treat-
ments are compared within each subject and then
summarized across subjects. The crossover
design is different from the blocked design
described above in that each block consists of a
single subject, which means that measurements
within each block are not independent of each
other. Furthermore, it is possible that a residual
effect of one drug carries over to impact the effect
of another drug administered subsequently. Statis-
tical analytical methods are limited in their ability
to adjust and correct for such effects. This is why
the use of crossover designs in clinical research is
limited.
In summary, the design of a clinical trial incor-
porates methods of minimizing noise and the pre-
vention of bias. This is done through the use of
appropriate subject allocation procedures, such as
randomization and blinding or through the use of
stratification and blocking.

25.7 The study population:

inclusion and exclusion

criteria

Generalizability

The study of the pharmaceutical effect of a drug
is always done in reference to a population of

prospective patients. For example, the clinical

dose to be recommended for an older patient is

often different than for a younger patient. Thus, the

target population for the study must bewell defined

in advance. Obviously, it is impractical to study the

entire patient population of interest. Fortunately,

this is also not necessary. Statistical sampling

methodology enables us to draw conclusions

from a sample to the population from which the

sample had been drawn, to any desirable degree of

accuracy and confidence. But, there is one impor-

tant caveat to this ability: The sample must be

‘representative’ of the population of interest;

meaning that the sample must preserve all the

relevant characteristics of the population. That is,

samples shouldhavethesimilar proportionsofmen

and women, similar racial composition, similar

numbers of hypertensive patients and so on.

Clearly, the creation of an exact replica of the

population on a small scale is an impossible task.

However, statistical sampling methods can pro-

duce very close to representative samples with

very high probability. These are the methods uti-

lized by pollsters to make highly reliable predic-

tions and inferences on the population from

relatively small samples.

In clinical research, the random selection of

subjects to be included in the trial from the target

population is not practical. Subjects are usually

selected from the patient pools available to the

investigators participating in the trial. This, in

and of itself, is problematic. The subject pool

available to a particular center usually reflects

the population in the geographical area where the

center is located which may not represent the

general potential patient population. To compli-

cate things even further, some of the subjects

available at a given center may not be suitable

for enrollment in a trial with an experimental

drug. The investigator may wish to exclude cer-

tain subjects because of certain known or

unknown risks. The possible effects of drugs on

the unborn fetus are often unknown, and thus

pregnant or lactating women are usually

excluded. Potential subjects may be excluded if

they are taking another medication, which can

potentially interact with the study drug. Also,

some potential subjects may refuse to participate

25.7 THE STUDY POPULATION: INCLUSION AND EXCLUSION CRITERIA 323