in the trial for one reason or other. Finally, for the
purpose of studying the efficacy of a drug, it is
desirable to enroll only subjects who are most
likely to have a measurable response to treat-
ment. Thus, every trial protocol contains a list
of inclusion and exclusion criteria defining the
subject population to be studied. Obviously, such
a population is hardly ever fully representative
of the target population. This raises a question
regarding the generalizability of the trial’s
conclusions.
When defining a set of inclusion and exclusion
criteria for a trial, the issue of generalizability must
be kept in mind. The rule is that the more restrictive
the criteria, the less generalizable the results. On
the contrary, setting criteria for eligibility to parti-
cipate in the trial provides the investigator with an
important tool for controlling the variability. Thus,
the choice of eligibility criteria must guided so as to
balance the efficiency of the trial design against the
need to assure that the result are generalizable.
Some of the guiding principles for defining sub-
jects’ eligibility are listed below.
Homogeneity
Homogeneity of the subject population is an
important factor in controlling variability. The
more homogeneous the subject population gener-
ating the data, the more informative it is. Thus,
fewer subjects are required to achieve the desired
control of the statistical errors when a study is
conducted in a homogeneous subject population
as compared to when the subjects are drawn from a
heterogeneous population. The problem is that the
more homogenous the group of subjects, the less
representative of the general potential patient
population it is. In the early stages of drug devel-
opment, where the goal is to establish the general
perimeters for the drug safety and efficacy, and
provide information for the design of future stu-
dies, studies are usually carried out on a limited
number of subjects. In these early trials, it is the
subjects’ safety that is of primary concern, and
the question of efficacy is secondary. The scope
of the efficacy-related questions is limited to the
‘proof of principle’, that is, a demonstration of
clinical activity, the identification of a safe dose
range and information leading to the choice of dose
and regimen for further studies. Subjects are
selected who are most likely to respond to treat-
ment, present no obvious potential safety risks and
are as similar as possible. Later stage studies such
as confirmative phase III trials, those providing
pivotal information for the proof of the drug’s
efficacy and safety, are generally less restrictive.Safety
The safety of the subjects enrolled in the trial is
always the primary concern of the researcher. Indi-
viduals at high or unknown risk to treatment with
the drug are excluded from the study. For example,
women of child bearing potential are usually
excluded or required to use an acceptable method
of birth control. Similarly, patients who are taking
medications that might interact with the experi-
mental drug, or who have medical conditions that
place themat increased risk,are alsoexcluded from
participation.Selection of subjects – maximizing
the signal-to-noise ratioClinical trials are very expensive undertakings.
Also, because they involve human subjects, there
is always an ethical imperative to use the subject
resources judiciously. Often, the researcher has
only one chance to conduct a trial designed to
answer a given question. Thus, the efficiency of
the trial design is critical. In other words, the design
must be such that the signal-to-noise ratio is max-
imized. The selection of subjects by specifying
certain inclusion and exclusion criteria may go a
long way in this direction. The exclusion of
patients with poor prognosis who are unlikely to
respond to treatment, the inclusion of only patients
with more than minimal severity of their condition
and similar measures are often used to achieve this
goal. Again, one must be careful not to narrow
the subject population to the extent that the
results could not be generalized to a broader patient
population.324 CH25 STATISTICAL PRINCIPLES AND APPLICATION IN BIOPHARMACEUTICAL RESEARCH