Statistical Methods in Medical Research 4ed

18 Clinical trials
18.1 Introduction
Clinical trials are controlled experiments to compare the efficacy and safety, for
human subjects, of different medical interventions. Strictly, the term clinical
implies that the subjects are patients suffering from some specific illness, and
indeed many, or most, clinical trials are conducted with the participation of
patients and compare treatments intended to improve their condition. However,
the term clinical trial is often used in a rather wider sense to include controlled
trials of prophylactic agents such as vaccines on individuals who do not yet suffer
from the disease under study, and for trials of administrative aspects of medical
care, such as the choice of home or hospital care for a particular type of patient.
Cochrane (1972), writing particularly about the latter category, used the term
randomized controlled trial (RCT).
Since a clinical trial is an experiment, it is subject to the basic principles of
experimentation (§9.1), such as randomization, replication and control of variability.
However, the fact that the experimental units are human subjects calls for
special consideration and gives rise to many unique problems. First, in clinical
trials patients are normally recruited over a period of time and the relevant
observations accrue gradually. This fact limits the opportunity to exploit the
more complex forms of experimental design in which factors are balanced by
systems of blocking; the designs used in trials are therefore relatively simple.
Secondly, there are greater potentialities for bias in assessing the response to
treatment than is true, for instance, of most laboratory experiments; we consider
some of these problems in §18.5. Thirdly, and perhaps most importantly, any
proposal for a clinical trial must be carefully scrutinized from an ethical point of
view, for no doctor will allow a patient under his or her care to be given a
treatment believed to be clearly inferior, unless the condition being treated is
extremely mild. There are many situations, though, where the relative merits of
treatments are by no means clear. Doctors may then agree to random allocation,
at least until the issue is resolved. The possibility that the gradual accumulation
of data may modify the investigator's ethical stance may lead to the adoption of
a sequential design (§18.7).
Trials intended as authoritative research studies, with random assignment,
are referred to as Phase III. Most of this chapter is concerned with Phase III
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