A clinical trial is a prospective study designed to determine the effectiveness of a treatment, a surgical procedure, or a therapeutic regimen administered to patients with a specific disease. Usually, the new drug or surgical procedure is first experimented on laboratory animals. If a tolerated dose can be determined and the drug or surgical procedure is considered to have potential efficacy, clinical trials on humans are warranted.
The sequence of therapeutic clinical trials are given below:
Figure: Sequence of Clinical Trials.
Different Types of Clinical Trials or Phase of Clinical Trial:
Following are the different types of clinical trials:
a) Phase I trials
b) Phase II trials
i. Phase II A trials
ii. Phase II B trials
c) Phase III trials
Following are the different types of clinical trials:
a) Phase I trials
b) Phase II trials
i. Phase II A trials
ii. Phase II B trials
c) Phase III trials
a) Phase I Trials:
A phase I or early trials, is an exploratory investigation of one of several surgical procedures or therapeutic regimens with different types of patients in search of one that can be used in later studies. Very few treatments are totally free of undesired side effects or without any hazard to the patients. For instance, almost all anticancer drugs designed to destroy cancer cells are also harmful to normal cells.
In general, the major objective of a phase I trial is to establish a maximum tolerated dose (MTD) for a new drug. The MTD will then be used in subsequent clinical trials to determine efficacy (Phase II) and to compare with other drugs (Phase III).
b) Phase II Trials:
In a two stage procedure, if no effect is noted in phase I, a phase IIA trial may be under taken. After a treatment is found to be effective in phase IIA, a phase IIB trial should be conducted. If the treatment is found to be ineffective again in phase IIB, it would be considered unworthy of further study.
The objective of phase IIA or preliminary trial is to decide if a particular therapeutic regimen is effective enough to warrant further study. The decision to be reached at the end of the preliminary trial is one of the two possibilities:
1. The treatment is unlikely to be effective in percent of patients or more.
2. The treatment could be effective in percent of patients or more.
c) Phase III Trials:
A phase III trial or comparative clinical trial is a planned experiment or human subjects involving two or more treatments in which the primary purpose is to determine the relative merits of the treatments. It is undertaken after the treatment has successfully passed a phase II trial.
A phase I or early trials, is an exploratory investigation of one of several surgical procedures or therapeutic regimens with different types of patients in search of one that can be used in later studies. Very few treatments are totally free of undesired side effects or without any hazard to the patients. For instance, almost all anticancer drugs designed to destroy cancer cells are also harmful to normal cells.
In general, the major objective of a phase I trial is to establish a maximum tolerated dose (MTD) for a new drug. The MTD will then be used in subsequent clinical trials to determine efficacy (Phase II) and to compare with other drugs (Phase III).
b) Phase II Trials:
In a two stage procedure, if no effect is noted in phase I, a phase IIA trial may be under taken. After a treatment is found to be effective in phase IIA, a phase IIB trial should be conducted. If the treatment is found to be ineffective again in phase IIB, it would be considered unworthy of further study.
The objective of phase IIA or preliminary trial is to decide if a particular therapeutic regimen is effective enough to warrant further study. The decision to be reached at the end of the preliminary trial is one of the two possibilities:
1. The treatment is unlikely to be effective in percent of patients or more.
2. The treatment could be effective in percent of patients or more.
c) Phase III Trials:
A phase III trial or comparative clinical trial is a planned experiment or human subjects involving two or more treatments in which the primary purpose is to determine the relative merits of the treatments. It is undertaken after the treatment has successfully passed a phase II trial.
Considerations in Planning Clinical Trials these things are to be considered, such as 1. Time for Planning, 2. Number of Treatments Involved, 3. Duration of the Trial, 4. Comparability of patients, 5. Treatment allocation ratio, 6. Use of a concurrent or Historical control group, 7. Treatment management, 8. Ethical considerations
The information below must be well defined in the clinical trial:
1) Purpose of the clinical trial
2) Status of investigation drug, device or procedure.
3) Description of the clinical trial including all of the procedures involved
4) Potential benefits to the participants
5) Possible risks to the participants
6) Information concerning medical treatment and compensation in the event of injury or adverse effect.
7) Confidentiality and methods used to protect confidentiality.
1) Purpose of the clinical trial
2) Status of investigation drug, device or procedure.
3) Description of the clinical trial including all of the procedures involved
4) Potential benefits to the participants
5) Possible risks to the participants
6) Information concerning medical treatment and compensation in the event of injury or adverse effect.
7) Confidentiality and methods used to protect confidentiality.
Designs for Comparative Trials in Clinical Trials:
There are two types of experimental designs of comparative clinical trials such as 1. Fixed sample trials and 2. Sequential trials.
1. Fixed Sample Trials:
In fixed sample trials, the number of patients allocated to the two (or more) treatments is fixed before the study begins. Some of the fixed sample designs are: a) Simple Randomized design, b) Stratified Randomized design, c) Cross over design, d) Factorial design
a) Simple Randomized Design:
In this case patients are randomly assigned to the two (or more) treatments without considering their characteristics. Usually, the randomization is restricted to a fixed number of patients and each treatment group will be equal in size. The main advantage of this design is its simplicity and usefulness when important prognostic factors are unknown or the potential subjects are homogeneous with respect to patient characteristics. Its disadvantage is possible non comparability among treatment groups and based analysis.
b) Stratified Randomized Design:
If important prognostic factors are known and patients can be grouped into prognostic categories or strata, comparability among treatment groups can be achieved. Within each stratum, patients are randomly assigned to the treatments.
c) Crossover Design:
A crossover design is a combination of the simple randomized design and the paired comparison design. The crossover design is good in measuring short term relief of signs or symptoms. It does allow more precise comparison of the treatments. The major problem is the assumption of no carry over effect. If the assumption is violated, the design is insensitive in detecting treatment differences.
d) Factorial Design:
In a factorial design, one of the two treatments is administered at levels, the other at levels. The goal is to test various treatment effects as well as possible interaction effects. The simplest factorial design is a design, in which two treatments are studied for their relationship to response and each is given at two levels, say at high dosage and low dosage. If the number of treatments and the number of levels are large, many patients would be required and the results might be difficult to interpret.
2. Sequential Trials:
In sequential trials, the decision whether to continue taking new patients is determined by the results accumulated to that time. Sequential designs are:
a) Open sequential design
b) Closed sequential design.
There are two types of experimental designs of comparative clinical trials such as 1. Fixed sample trials and 2. Sequential trials.
1. Fixed Sample Trials:
In fixed sample trials, the number of patients allocated to the two (or more) treatments is fixed before the study begins. Some of the fixed sample designs are: a) Simple Randomized design, b) Stratified Randomized design, c) Cross over design, d) Factorial design
a) Simple Randomized Design:
In this case patients are randomly assigned to the two (or more) treatments without considering their characteristics. Usually, the randomization is restricted to a fixed number of patients and each treatment group will be equal in size. The main advantage of this design is its simplicity and usefulness when important prognostic factors are unknown or the potential subjects are homogeneous with respect to patient characteristics. Its disadvantage is possible non comparability among treatment groups and based analysis.
b) Stratified Randomized Design:
If important prognostic factors are known and patients can be grouped into prognostic categories or strata, comparability among treatment groups can be achieved. Within each stratum, patients are randomly assigned to the treatments.
c) Crossover Design:
A crossover design is a combination of the simple randomized design and the paired comparison design. The crossover design is good in measuring short term relief of signs or symptoms. It does allow more precise comparison of the treatments. The major problem is the assumption of no carry over effect. If the assumption is violated, the design is insensitive in detecting treatment differences.
d) Factorial Design:
In a factorial design, one of the two treatments is administered at levels, the other at levels. The goal is to test various treatment effects as well as possible interaction effects. The simplest factorial design is a design, in which two treatments are studied for their relationship to response and each is given at two levels, say at high dosage and low dosage. If the number of treatments and the number of levels are large, many patients would be required and the results might be difficult to interpret.
2. Sequential Trials:
In sequential trials, the decision whether to continue taking new patients is determined by the results accumulated to that time. Sequential designs are:
a) Open sequential design
b) Closed sequential design.
a) Open Sequential Design:
In this classical sequential procedure, patients are entered in the study in pairs; one is randomly assigned to receive treatment and the other treatment and preference of treatment is then recorded for each pair.
b) Close Sequential Design:
This the design suggested by Armitage (1975). The main difference between this design and the open design is that is allows the investigator to terminate the trial concluding no preference between the two treatments.
Advantages of Sequential Trial :
a) Sample sizes are on the average smaller than for the fixed sample procedures.
b) An early decision may be reached if there is a strong prior evidence that one of the treatments is more effective than the other.
c) In most cases, sequential trials are easy to carry out.
Disadvantages of Sequential Trial :
a) Results from patients may not be available soon enough for decisions of whether to continue the trial. For example, if the response is survival time, months or years may elapse before an outcome can be determined.
b) Although sample sizes are, on the average, smaller that in fixed sample trials, there is no guarantee. In some situations, sequential trials also require a large number of patients.
c) If an early decision is made from a small number of patients, the effectiveness of the treatments can only be estimated from the small group of patients.
In this classical sequential procedure, patients are entered in the study in pairs; one is randomly assigned to receive treatment and the other treatment and preference of treatment is then recorded for each pair.
b) Close Sequential Design:
This the design suggested by Armitage (1975). The main difference between this design and the open design is that is allows the investigator to terminate the trial concluding no preference between the two treatments.
Advantages of Sequential Trial :
a) Sample sizes are on the average smaller than for the fixed sample procedures.
b) An early decision may be reached if there is a strong prior evidence that one of the treatments is more effective than the other.
c) In most cases, sequential trials are easy to carry out.
Disadvantages of Sequential Trial :
a) Results from patients may not be available soon enough for decisions of whether to continue the trial. For example, if the response is survival time, months or years may elapse before an outcome can be determined.
b) Although sample sizes are, on the average, smaller that in fixed sample trials, there is no guarantee. In some situations, sequential trials also require a large number of patients.
c) If an early decision is made from a small number of patients, the effectiveness of the treatments can only be estimated from the small group of patients.
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