Clinical Trials

A clinical trial is defined as ". . . an experiment performed by a health care organization or professional to evaluate the effect of an intervention or treatment against a control in a clinical environment. It is a prospective study to identify outcome measures that are influenced by the intervention. A clinical trial is designed to maintain health, prevent diseases, or treat diseased subjects. The safety, efficacy, pharmacological, pharmacokinetic, quality-of-life, health economics, or biochemical effects are measured in a clinical trial." (Chow, 2000, p. 110).

Clinical trials are conducted with human subjects (who are usually patients). Before the patients can be enrolled in the trial, they must be informed about the perceived benefits and risks. The process of apprising the patients about benefits and risks is accomplished by using an informed consent form that the patient must sign. Each year in the United States, many companies perform clinical trials. The impetus for these trials is the development of new drugs or medical devices that the companies wish to bring to market. A primary objective of these clinical trials is to demonstrate the safety and effectiveness of the products to the FDA.

Clinical trials take many forms. In a randomized, controlled clinical trial, patients are randomized into treatment and control groups. Sometimes, only a single treatment group and a historical control group are used. This procedure may be followed when the use of a concurrent control group would be expensive or would expose patients in the control group to undue risks. In the medical device industry, the control also can be replaced by an objective performance criterion (OPC). Established standards for current forms of available treatments can be used to determine these OPCs. Patients who undergo the current forms of available treatment thus constitute a control group. Generally, a large amount of historical data is needed to establish an OPC.

Concurrent randomized controls are often preferred to historical controls because the investigators want to have a sound basis for attributing observed differences between the treatment and control groups to treatment effects. If the trial is conducted without concurrent randomized controls, statisticians can argue that any differences shown could be due to differences among the study patient populations rather than to differences in the treatment. As an example, in a hypothetical study conducted in Southern California, a suitable historical control group might consist of Hispanic women. However, if the treatment were intended for males as well as females (including both genders from many other races), a historical control group comprised of Hispanic women would be inappropriate. In addition, if we then were to use a diverse population of males and females of all races for the treatment group only, how would we know that any observed effect was due to the treatment and not simply to the fact that males respond differently from females or that racial differences are playing a role in the response? Thus, the use of a concurrent control group would overcome the difficulties produced by a historical control group.

In addition, in order to avoid potential bias, patients are often blinded as to study conditions (i.e., treatment or control group), when such blinding is possible. It is also preferable to blind the investigator to the study conditions to prevent bias that could invalidate the study conclusions. When both the investigator and the patient are blinded, the trial is called double-blinded. Double-blinding often is possible in drug treatment studies but rarely is possible in medical device trials. In device trials, the patient sometimes can be blinded but the attending physician cannot be.

To illustrate the scientific value of randomized, blinded, controlled, clinical trials, we will describe a real trial that was sponsored by a medical device company that produces and markets catheters. The trial was designed to determine the safety and efficacy of direct myocardial revascularization (DMR). DMR is a clinical procedure designed to improve cardiac circulation (also called perfusion). The medical procedure involves the placement of a catheter in the patient's heart. A small laser on the tip of the catheter is fired to produce channels in the heart muscle that theoretically promote cardiac perfusion. The end result should be improved heart function in those patients who are suffering from severe symptomatic coronary artery disease.

In order to determine if this theory works in practice, clinical trials were required. Some studies were conducted in which patients were given treadmill tests before and after treatment in order to demonstrate increased cardiac output. Other measures of improved heart function also were considered in these studies. Results indicated promise for the treatment.

However, critics charged that because these trials did not have randomized controls, a placebo effect (i.e., patients improve because of a perceived benefit from knowing that they received a treatment) could not be ruled out. In the DMR DIRECT trial, patients were randomized to a treatment group and a sham control group. The sham is a procedure used to keep the patient blinded to the treatment. In all cases the laser catheter was placed in the heart. The laser was fired in the patients randomized to the DMR treatment group but not in the patients randomized to the control group. This was a single-blinded trial; i.e., none of the patients knew whether or not they received the treatment. Obviously, the physician conducting the procedure had to know which patients were in the treatment and control groups. The patients, who were advised of the possibility of the sham treatment in the informed consent form, of course received standard care for their illness.

At the follow-up tests, everyone involved, including the physicians, was blinded to the group associated with the laser treatment. For a certain period after the data were analyzed, the results were known only to the independent group of statisticians who had designed the trial and then analyzed the data.

These results were released and made public in October 2000. Quoting the press release, "Preliminary analysis of the data shows that patients who received this laser-based therapy did not experience a statistically significant increase in exercise times or a decrease in the frequency and severity of angina versus the control group of patients who were treated medically. An improvement across all study groups may suggest a possible placebo effect."

As a result of this trial, the potential benefit of DMR was found not to be significant and not worth the added risk to the patient. Companies and physicians looking for effective treatments for these patients must now consider alternative therapies. The trial saved the sponsor, its competitors, the patients, and the physicians from further use of an ineffective and highly invasive treatment.

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