CLINICAL TRIAL

Irawan Yusuf

06/29/16
Copyright 1996-98 Dale Carnegie & Associates, Inc.

INTRODUCTION
What are Clinical Trials and Why Investigate Them?
Scientific discoveries are providing more and more insights
into the causes of diseases. Many of these successes are
limited to the laboratory and have yet to be translated into
improved care for people with diseases.
A clinical trial is a test of a new treatment in patients.
Medicine is extremely conservative in nature, and it takes
many years for a treatment to become generally available
even after it has shown promising results in patients.
Clinical trials are a critical part of the research process.
Clinical trials help to move basic scientific research from
the laboratory into treatments for people. By evaluating
the results of these trials, we can find better treatments
and ways to prevent, detect, and treat diseases.

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INTRODUCTION
Clinical trials are research studies involving
people.They seek to answer specific scientific
questions to find better ways to prevent,
detect, and treat diseases, and to improve care
for people with diseases.
Clinical trials differ by type of trial and phase
of trial. Each clinical trial follows a set of strict
scientific guidelines called a protocol.
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Why Do Clinical
Trial?
To answer clinical problems
To gain new knowledge about a
new or established treatment
To support claim
For gaining
approval

government

For
marketing
technique

drug,

regulatory
device

or
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LEARNING OBJECTIVES
By reading this section and completing
the exercises, you will be able to:
Define clinical trials
Name the different types and phases of
clinical trials
Describe how participants are assigned
to groups in "randomized" clinical trials
Review the purpose of a clinical trial
protocol and its importance.
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TYPES CLINICAL TRIALS

Treatment trials
What new treatment approaches
help people who have cancer?

can

What is the most effective treatment for

people who have cancer?
Prevention trials
What approaches can prevent a specific
type of cancer from developing in people
who have not previously had cancer?
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TYPES OF CLINICAL
TRIALS
Early-detection/screening trials
What are new ways of finding cancer in people
before they have any symptoms?
Diagnostic trials
How can new tests or procedures identify cancer
more accurately and at an earlier stage?
Quality-of-life/supportive care trials
What kind of new approaches can improve the
comfort and quality of life of people who have
cancer?

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PHASES CLINICAL
TRIALS
Phase 1 Trials
Phase 2 Trials
Phase 3 Trials
Phase 4 Trials
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PHASES CLINICAL
TRIALS
Phase 1
Number of
participants

Purpose

15-30

To find a safe
dosage
To design how
the drug should
be given
To observe how
the drug affects
the human body

Phase 2
<100

Phase 3
>100 thousands

To determine if
the drug has an
effect
on
particular
diseases

To compare a
new drug with
current standard
treatment

Phase 4
Several thousands

To
further
evaluate
longterm safety and
effectiveness of
new drugs

To observe how
the drug affects
the human body

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PHASE 1 TRIALS
Once laboratory studies show that a new
approach has promise, a phase 1 trial can
begin. A phase 1 trial is the first step in
testing a new drugs in humans.
The goal of the Phase I trial is not to see
how well a new treatment works but rather
just to discover how much of the drug can
be given safely, and to understand its side
effects and chemistry in the body.
These trials most closely fit the stereotype
of a truly experimental treatment.
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PHASE 1 TRIALS
Primary Objectives
A Phase 1 trial is a dose finding study
where the primary objective is to
determine the Maximum Tolerated Dose
(MTD) of the treatment and to define the
toxicities of the treatment.
The classic Phase 1 trial is only intended
to determine the dose and characterize
the side effects, not to show whether the
treatment is effective, but, of course, if
it turns out the treatment actually is
effective, patients can still benefit.

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PHASE 1 TRIALS
Standard Design
The standard Phase 1 design is a Dose Escalation
trial in which successive small groups of patients
(Called "cohorts") are given successively higher
doses of the treatment until some of the patients
in a cohort experience unacceptable side effects
If unacceptable side effects are not seen in the first
cohort, the next cohort gets a higher dose. This
continues until a dose is reached which is too toxic
for a set fraction of patients, say one in three. Then
the previous dose level is considered to be the
Maximum Tolerated Dose (MTD).
Many Phase 1 studies are single institution studies.

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PHASE 2 TRIALS
Primary Objectives
Phase 2 trials test the ability of the treatment to
produce measurable effects in a small to medium
sized group of patients (typically <100), all with
the same kind of disease. A Phase 2 trial is the
first test directed at any measure of efficacy.
The specific statistic measured is the response
rate. Patients who achieve at least a 50%
reduction in the total size of their measurable
tumors are considered to have responded. If
some tumor remains, it is considered to be a
partial response (PR), but if no detectable tumor
remains it is called a complete response (CR).

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PHASE 2 TRIALS
Standard Design
One Stage Design: In the simplest Phase 2 trial, a predetermined number patients with the same type of
diseases are given the treatment at the dose determined
in the prior Phase 2 trial, and the response rate is
measured.
Two Stage Design: Many Phase 2 trials conducted in two
stages. The idea is to avoid giving patients a treatment as
soon as it can be known that the treatment is ineffective.
In the two stage design, after a pre-determined number of
patients have been treated, the trial is paused, and the
response rate is evaluated. If the response rate is less
than a prespecified minimum goal, it's concluded that the
treatment is not worth pursuing and the trial is ended.
Many, but not all, Phase 2 studies are multi-center studies.

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PHASE 3 TRIALS
Primary Objectives
Phase 3 trials compare two treatments for a
particular
kind
of
diseases.
Typically
an
experimental treatment is compared to a standard
treatment. The usual objective is to see if the new
treatment produces better survival than the old one
In some cases the objective is to show that a
treatment with lesser side-effects is at least as good
as the standard treatment.
Finally, Phase 3 trials are used to compare
treatments in common use where there is significant
uncertainty or controversy over which is better.
Almost all modern Phase 3 trials also compare
"Quality of Life" (QOL) with the different treatments.

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PHASE 3 TRIALS
Standard Design
The standard Phase 3 trial randomizes the
patients between the treatments being tested in
the trial.
The purpose of randomization is to eliminate any
potential systematic difference between patients
in the arms of the trial. If patients or their
doctors choose their treatment, there might be
some difference in the patients who entered one
arm compared to those who selected the other.
Randomly assigning patients to treatment would
be unethical if it were known in advance that one
of the treatments was inferior to the other,
simply because intentionally treating patients
with less than the best is unethical.
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PHASE 4 TRIALS
Phase 4 trials are used to further
evaluate the long-term safety and
effectiveness of a treatment.
Less common than phase 1, 2, and 3
trials, phase 4 trials take place after the
new treatment has been approved for
standard use (post-approval studies).
Further exploration of intervention
new indications or new uses of drug.
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RANDOMIZATION
How Participants Are Assigned in Randomized Trials
Phase 3 studies are randomized clinical trials. Some phase
2 trials may also be randomized.
Randomization is used to prevent bias in research.
Participants are assigned to either the investigational group
or the control group by chance, via a computer program, or
with a table of random numbers. Randomization ensures
that unknown factors do not influence the trial results.
The control group is made up of people who will get the
standard treatment for their disease.
The investigational group is made up of people who will get
the new drug being tested.

Anyone who is considering participation in a randomized

clinical trial needs to understand that she or he has an
equal chance to be assigned to one of the groups.

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RANDOMIZATION

Why Is Randomization
Important?
If participants or doctors choose a particular group
based on what they think is best, then one of the
groups would likely be very different than the
other, making comparison between the groups
difficult.
Randomization eliminates this bias because
participants have an equal chance of being
assigned to either group are as similar as possible.
Comparing similar groups of people taking different
treatments for the same type of disease is a way to
ensure that the study results are caused by the
treatments rather than by chance or other factors.

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GUIDING PRINCIPLES
Ethics
Scientific validity and integrity
Medical relevance
Regulatory
issues

and

medicolegal

Cost
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WHAT IS STEP ONE?

Start it with hypothesis
Must be in the form of statement

Then turn
question

it

into

The
questions
answerable

specific

must

be

This forms the basis of the study

objectives
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CLINICAL TRIAL PROTOCOL

Clinical trials
guidelines.

follow

strict

scientific

These guidelines clearly state the study's

design and who will be able to participate
in the study. Every trial has a person in
charge, usually a doctor, who is called the
principal investigator.
The principal investigator prepares a plan
for the study, called a protocol, which acts
like a "recipe" for conducting a clinical trial.
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CLINICAL TRIAL PROTOCOL

Introduction and rationale
Study objectives: general and specific
Study design
Inclusion and exclusion criteria
Specific study protocols
Randomization
Intervention
Endpoints
Data analysis and statistics

Ethical considerations (Helsinki Declaration)

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Endpoints in Clinical Trial

An endpoint is what researchers will measure to evaluate
the results of a new treatment being tested in a clinical
trial. Research teams establish the endpoints of a trial
before it begins.
It is important to note that endpoints differ, depending on
the type and phase of the clinical trial. Examples of
endpoints are:
Toxicity
what are the harmful effects of the drug?

Clinical response
how does the disease respond to the treatment?

Survival
how long does the person live?

Quality of life
how does the treatment affect a person's
enjoyment of life and sense of well being?

overall

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