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CLINICAL TRIAL.

Copyright 1996-98 © Dale Carnegie & Associates, Inc.

Irawan Yusuf

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INTRODUCTIONWhat 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 government regulatory approval

– For marketing drug, device or technique

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LEARNING OBJECTIVESBy 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 can help people who have cancer?

– 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 Phase 2 Phase 3 Phase 4

Number of participants

15-30 <100 >100 –thousands Several thousands

Purpose To find a safe dosage

To design how the drug should be givenTo observe how the drug affects the human body

To determine if the drug has an effect on particular diseases

To observe how the drug affects the human body

To compare a new drug with current standard treatment

To further evaluate long-term safety and effectiveness of new drugs

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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 TRIALSPrimary 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 TRIALSStandard 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 TRIALSPrimary 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 TRIALSStandard Design• One Stage Design: In the simplest Phase 2 trial, a pre-

determined 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 TRIALSPrimary 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 TRIALSStandard 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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RANDOMIZATIONHow 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.

RANDOMIZATION

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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 and medicolegal

issues•Cost

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WHAT IS STEP ONE?• Start it with hypothesis

– Must be in the form of statement

• Then turn it into a specific question– The questions must be

“answerable”– This forms the basis of the study

“objectives”

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CLINICAL TRIAL PROTOCOL• Clinical trials follow strict scientific

guidelines. • 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 overall enjoyment of life and sense of well being?