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What are Clinical Trials?

A clinical trial is a research study designed to evaluate potential new treatment options. These studies are the result of a long and deliberate research process that often takes years. Clinical trials test the safety and effectiveness of new or modified drugs, new drug doses, unique approaches to surgery or radiation therapy, and varied combinations of treatments.

Definition of Clinical trials

Clinical trials:

Trials to evaluate the effectiveness and safety of medications or medical devices by monitoring their effects on large groups of people.

Clinical research trials may be conducted by government health agencies such as NIH, researchers affiliated with a hospital or university medical program, independent researchers, or private industry. Usually volunteers are recruited, although in some cases research subjects may be paid. Subjects are generally divided into two or more groups, including a control group that does not receive the experimental treatment, receives a placebo (inactive substance) instead, or receives a tried-and-true therapy for comparison purpose

Inconclusive clinical trial

Inconclusive clinical trial:

A clinical trial that shows that a new treatment is neither clearly superior nor clearly inferior to standard treatment.

Positive clinical trial

Positive clinical trial:

A clinical trial that shows that the new treatment has a large beneficial effect and is superior to standard treatment

Randomized clinical trial

Randomized clinical trial:

A clinical trial in which the participants are assigned randomly (by chance alone) to different treatments

Randomized controlled trial

Randomized controlled trial: (RCT) A study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. The control may be a standard practice, a placebo ("sugar pill"), or no intervention at all. Someone who takes part in a randomized controlled trial (RCT) is called a participant or subject. RCTs seek to measure and compare the outcomes after the participants receive the interventions. Because the outcomes are measured, RCTs are quantitative studies. In sum, RCTs are quantitative, comparative, controlled experiments in which investigators study two or more interventions in a series of individuals who receive them in random order. The RCT is one of the simplest and most powerful tools in clinical res Key Features of the Randomized Clinical Trial. The randomized clinical trial is characterized by two or more therapeutic treatment groups. These groups are sometimes referred to as arms, particularly in cancer trials. One treatment may be a placebo control in which a biologically-inert substance (in a drug trial) is used. Placebo controls cannot always be used because of ethical or practical constraints. Often, the "control" condition is the treatment is the standard of care which is then compared to experimental treatments. Psychologic and other potentially confounding variables can be controlled by coding the treatment in such a way that the subject cannot tell what it is; this is called a single-blind trial. The best control is where neither the subjects nor the investigators know which treatment a given subject is receiving; this is called a double-blind trial. Again, ethical or practical constraints may make blinding impossible.

Clinical Research Designs

A clinical trial is an experiment conducted with patients as subjects. The principles of good experimental design apply to clinical trials. The strongest experimental design (the "gold standard") is the randomized design in which subjects (patients) are randomly assigned to treatment groups. An important distinction in the purpose of clinical trials is that between therapeutic trials (comparing treatment methods) and prophylactic (or prevention) trials.

Key Features of the Randomized Clinical Trial

The randomized clinical trial is characterized by two or more therapeutic treatment groups. These groups are sometimes referred to as arms, particularly in cancer trials. One treatment may be a placebo control in which a biologically-inert substance (in a drug trial) is used. Placebo controls cannot always be used because of ethical or practical constraints. Often, the "control" condition is the treatment is the standard of care which is then compared to experimental treatments.

Psychologic and other potentially confounding variables can be controlled by coding the treatment in such a way that the subject cannot tell what it is; this is called a single-blind trial. The best control is where neither the subjects nor the investigators know which treatment a given subject is receiving; this is called a double-blind trial. Again, ethical or practical constraints may make blinding impossible.

Epidemiological (Nonrandomized) Research Designs Often, for ethical or practical reasons, it is not possible to conduct true randomized studies. For example, we could not ethically design a clinical experiment to test the hypothesis that cigarette smoking causes lung cancer. Study designs have been developed in the field of epidemiology which are used in situations in which randomization is impossible. The designs we will discuss here are the prospective or cohort study and the case-control study (sometimes referred to as the case-comparison study). In the simplest type of cohort prospective study two groups (cohorts) of subjects are identified, one of which is exposed to a clinical intervention, an environmental condition, or health risk factor, and the other group is not. Suppose we were interested in the putative effects of aspirin in reducing the likelihood of colon cancer. We could identify the subjects, follow them prospectively through time (ten years, lets say) and determine if those who took one aspirin per day show lower color cancer rates than those who did not (This study is obviously an oversimplification). The major disadvantage of the cohort study, compared to the randomized study, is that the groups may not be equivalent on other factors such as diet or smoking history. In the case-control study a group of patients who already have a disease or other outcome (the cases) is compared to another group of controls who do not. Thus, such studies are conducted retrospectively, not prospectively. Suppose we are interested in exposure to environmental tobacco smoke ("second-hand smoke") and its possible exacerbation of asthma in children. We could identify asthmatic children with exacerbated symptoms and determine the proportion of them exposed to environmental tobacco smoke. Then, we identify asthmatic children without the exacerbated symptoms and determine the proportion of them exposed to environmental tobacco smoke. Let us say the incidence (risk) of exacerbation for the exposed group was 2.3% and for the unexposed group was 1.3%. Typically, the relative risk is found in case-control studies. The relative risk is 2.3/1.3 or 1.8. Thus, in this study asthmatic children exposed to environmental tobacco smoke were 1.8 times as likely to show exacerbation of symptoms as were those not exposed. Case-control studies also have the disadvantage, compared to the randomized study, that the groups may not be equivalent on other factors. Nevertheless, case-control studies are highly valuable for studying diseases that take years to manifest themselves, such as many cancers.

Phases for the Clinical Trials (Drug Trials)

PHASE 1 DRUG TRIAL:

Phase 1 trials include the initial introduction of an investigational new drug into humans. These studies are typically conducted with healthy volunteers; sometimes, where the drug is intended for use in patients with a particular disease, however, such patients may participate as subjects. Phase 1 trials are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses (to establish a safe dose range), and, if possible, to gain early evidence of effectiveness; they are typically closely monitored. The ultimate goal of Phase 1 trials is to obtain sufficient information about the drug's pharmacokinetics and pharmacological effects to permit the design of well-controlled, sufficiently valid Phase 2 studies. Other examples of Phase 1 studies include studies of drug metabolism, structure-activity relationships, and mechanisms of actions in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects involved in Phase 1 investigations is generally in the range of 20-80.

PHASE 2 DRUG TRIAL:

Phase 2 trials include controlled clinical studies conducted to evaluate the drugs effectiveness for a particular indication in patients with the disease or condition under study, and to determine the common short-term side effects and risks associated with the drug. These studies are typically well-controlled, closely monitored, and conducted with a relatively small number of patients, usually involving no more than several hundred subjects.

PHASE 3 DRUG TRIAL:

Phase 3 trials involve the to determine the common short-term side effects and risks associated with the drug. They are performed after preliminary evidence of effectiveness has been obtained, and are intended to gather necessary additional information about effectiveness and safety for evaluating the overall benefit-risk relationship of the drug, and to provide an adequate basis for physician labeling. In Phase 3 studies, the drug is used the way it would be administered when marketed. When these studies are completed and the sponsor believes that the drug is safe and effective under specific conditions, the sponsor applies to the FDA for approval to market the drug. Phase 3 trials usually involve several hundred to several thousand patient-subjects.

PHASE 4 DRUG TRIAL:

Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain postmarketing (Phase 4) studies to delineate additional information about the drugs risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in Phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time. Clinical trials are an integral component for improving the treatment of medical conditions because they lead to higher standards of care.

In the United States all new cancer treatment products must proceed through an orderly clinical trials evaluation process to ensure that they have an acceptable level of safety and demonstrate benefit to helping patients with a specific disease before they become commercially available to other patients.

Clinical trials essentially fall into two general categories.

1. The first general category of clinical trials are designed to evaluate new drugs, compounds, or biologic agents that have not yet been approved by the Food and Drug Administration (FDA) for administration to patients.

All substances must go through several phases of clinical trials to document their safety and effectiveness before the FDA approves them for routine use to treat cancer patients. Prior to FDA approval, these substances are only available through clinical trials; however, after FDA approval, they are commercially available.

2. Clinical trials may also evaluate drugs, compounds, or biologic agents already approved by the FDA for the treatment of one type of disease.

These substances have already been determined to be safe by the FDA and they are now being evaluated in different doses, schedules, and combinations to determine how to optimally use them for the treatment of a variety of diseases. Development of new cancer agents and treatment strategies occurs in four phases. Each phase is designed to determine specific information about the potential new treatment such as its risks, safety and effectiveness compared to standard therapy. The hope is that the new therapy will be an improvement over the previous standard therapy.

Phase I Trials

(cancer treatment): This phase is probably the most important step in the development of a new drug or therapy. These trials usually involve a small number of patients for whom other standard therapies have failed or no known alternative therapy is available. Phase I therapy may produce anti-cancer effects and a small number of patients may benefit. However, the primary goals of this phase are to determine anticancer activity in humans, the maximum tolerated dose of the treatment, the manner in which the drug works in the body, the toxic side effects related to different doses and whether toxic side effects are reversible. Upon completion of phase I trials, the information that has been gathered is used to begin phase II trials.

Phase II Trials:

Once the information is gathered and analyzed from phase I trials, phase II trials are designed to determine the effectiveness of the treatment in a specific patient population at the dose and schedules determined in phase I. These trials usually require a slightly higher number of patients than phase I trials. This number may increase depending on the number of responses as the phase II trial progresses. Drugs or therapies that are shown to be active in phase II trials may become standard treatment or be further evaluated for effectiveness in phase III trials.

Phase III Trials:

Phase III trials compare a new drug or therapy with a standard therapy in a randomized and controlled manner in order to determine proof of effectiveness. Phase III trials require a large number of patients to measure the statistical validity of the results because patient age, sex, race, and other unknown factors could affect the results. To obtain an adequate number of patients, several physicians (investigators) from different institutions typically participate in phase III clinical trials.

Phase IV Trials: Once the drug or treatment becomes part of standard therapy, the manufacturer of the drug may elect to initiate phase IV trials. This phase includes continued evaluation of the treatment effectiveness and monitoring of side effects as well as implementing studies to evaluate usefulness in different types of cancers.