From Wikipedia,
the free encyclopedia
In
medicine, a clinical trial
(synonyms: clinical studies,
research protocols, medical
research) is a research study.
Types of clinical trials
The most commonly performed
clinical trials evaluate new
drugs, medical devices,
biologics, or other interventions
to patients in strictly
scientifically controlled
settings, and are required for
Food and Drug Administration
approval of new therapies. Trials
may be designed to assess the
safety and efficacy of an
experimental therapy, to assess
whether the new intervention is
better than standard therapy, or
to compare the efficacy of two
standard or marketed
interventions.
To be ethical, they must
involve the full and
informed consent of
participating human subjects. They
are closely supervised by
appropriate regulatory
authorities. All interventional
studies must be approved by an
ethics committee before
permission is granted to run the
trial.
The study design that provides
the most compelling evidence of a
causal relationship between the
treatment and the effect, is the
randomized controlled trial.
Studies in
epidemiology such as the
cohort study and the
case-control study are
clinical studies in that they
involve human participants, but
provide less compelling evidence
than the randomized controlled
trial. The major difference
between clinical trials and
epidemiological studies is that,
in clinical trials, the
investigators manipulate the
administration of a new
intervention and measure the
effect of that manipulation,
whereas epidemiological studies
only observe associations
(correlations) between the
treatments experienced by
participants and their health
status or diseases.
Currently some Phase II and
most Phase III drug trials are
designed to be randomized,
double-blind, and
placebo-controlled. This means
that each study subject is
randomly assigned to receive one
of the treatments, which might be
the placebo. Neither the subjects
nor scientists involved in the
study know which study treatment
is being administered to any given
subject; and, in particular, none
of those involved in the study
know which subjects are being
administered a placebo. Of note,
during the last ten years or so it
has become a common practice to
conduct "active comparator" trials
(also known as "active control"
trials) - in other words, when a
treatment exists that is clearly
better than doing nothing (i.e.
the placebo) for the subject, the
alternate treatment would be a
standard-of-care therapy.
While the term clinical trials
is most commonly associated with
large randomized studies, many
clinical trials are small. They
may be initiated by single
physicians or a small group of
physicians, and are designed to
test simple questions. Other
clinical trials require large
numbers of participants followed
over long periods of time. It is
sometimes necessary to organize
multicenter trials. Often the
centres taking part in such trials
are in different countries (in
which case they may be termed
international clinical trials).
The number of patients enrolled
in the study also has a large
bearing on the ability of the
trial to reliably detect an effect
of a treatment. This is described
as the "power"
of the trial. It is usually
expressed as the probability that,
if the treatments differ in their
effect on the outcome of interest,
the statistical analysis of the
trial data will detect that
difference. The larger the sample
size or number of participants,
the greater the statistical power.
However, in designing a clinical
trial, this consideration must be
balanced with the greater costs
associated with larger studies.
The power of a trial is not a
single, unique value; it estimates
the ability of a trial to detect a
difference of a particular size
(or larger) between the treated
and control groups. For example,
of a lipid-lowering drug with 100
patients per group, might have a
power of .90 to detect a
difference between active and
placebo of 10 mg/dL or more, but
only have a power of .70 to detect
a difference of 5 mg/dL.
Phases
Pharmaceutical clinical trials
are commonly classified into four
phases, and the drug-development
process will normally proceed
through all four stages over many
years. If the drug successfully
passes through the first three
phases, it will usually be
successfully approved for use in
the general population.
Before
pharmaceutical companies start
clinical trials on drugs,
extensive
pre-clinical studies are
conducted.
Phase I
Phase I trials are the
first-stage of testing in human
subjects. Normally a small (20-80)
group of healthy volunteers will
be selected. This phase includes
trials designed to assess the
safety, tolerability,
pharmacokinetics, and
pharmacodynamics of a therapy.
These trials are almost always
conducted in an inpatient clinic,
where the subject can be observed
by full-time medical staff. The
subject is usually observed until
several half-lives of the drug
have passed. Phase I trials also
normally include dose-ranging
studies such that doses for
clinical use can be refined. The
tested range of doses will usually
be a small fraction of the dose
that causes harm in animal
testing. Phase I trials most often
include healthy volunteers,
however there are some
circumstances when patients are
used, such as with oncology
(cancer) and HIV drug trials. In
Phase I trials of new cancer
drugs, for example, patients with
advanced (metastatic) cancer are
used. These trials are usually
offered to patients who have had
other types of therapy and who
have few, if any, other treatment
choices.
There are two specific kinds of
Phase I trials - SAD studies, and
MAD studies.
SAD - Single Ascending Dose
studies are those in which groups
of three or six patients are given
a small dose of the drug and
observed for a specific period of
time. If they do not exhibit any
adverse side effects, a new group
of patients is then given a higher
dose. This is continued until
intolerable side effects start
showing up, at which point the
drug is said to have reached the
Maximum tolerated dose (MTD).
MAD - Multiple Ascending Dose
studies are conducted to better
understand the pharmacokinetics/pharmacodynamics
of the drug. In these studies, a
group of patients receives a low
dose of the drug and the dose is
subsequently escalated upto a
predetermined level. Samples (of
blood, and other fluids) are
collected at various time points
and analyzed to understand how the
drug is processed within the body.
Phase II
Once the initial safety of the
therapy has been confirmed in
Phase I trials, Phase II trials
are performed on larger groups
(100-300) and are designed to
assess clinical efficacy of the
therapy; as well as to continue
Phase I assessments in a larger
group of volunteers and patients.
The development process for a new
drug commonly fails during Phase
II trials due to the discovery of
poor efficacy or toxic effects.
Some trials in combine Phase I
and Phase II into a single trial,
monitoring both efficacy and
toxicity.
Phase III
Phase III studies are large
double-blind randomized controlled
trials on large patient groups
(1000-3000 or more) and are aimed
at being the definitive assessment
of the efficacy of the new
therapy, especially in comparison
with currently available
alternatives. Phase III trials are
the most expensive, time-consuming
and difficult trials to design and
run; especially in therapies for
chronic conditions. Once a drug
has proven satisfactory over Phase
III trials, the trial results are
usually combined into a large
document containing a
comprehensive description of the
methods and results of human and
animal studies, manufacturing
procedures, formulation details,
and shelf life. This collection of
information makes up the
"regulatory submission" that is
provided for review to various
regulatory authorities in
different countries, such as the
Therapeutic Goods Administration
(TGA) in Australia, the
European Medicines Agency (EMEA)
or the
Food and Drug Administration
(FDA) in the United States for
marketing approval.
Phase IV
Phase IV trials involve the
post-launch safety surveillance
and ongoing technical support of a
drug. Phase IV studies may be
mandated by regulatory authorities
or may be undertaken by the
sponsoring company for competitive
or other reasons. Post-launch
safety surveillance is designed to
detect any rare or long-term
adverse effects over a much
larger patient population and
timescale than was possible during
the initial clinical trials. Such
adverse effects detected by Phase
IV trials may result in the
withdrawal or restriction of a
drug - recent examples include
cerivastatin (brand names
Baycol and Lipobay),
troglitazone (Rezulin) and
rofecoxib (Vioxx).
References
- Rang HP, Dale MM, Ritter JM,
Moore PK (2003). Pharmacology
5 ed. Edinburgh: Churchill
Livingstone.
ISBN 0-443-07145-4
- Finn R, (1999). "Cancer
Clinical Trials: Experimental
Treatments and How They Can Help
You." Sebastopol: O'Reilly &
Associates.
ISBN 1-56592-566-1
